Inflammation

Question 1

What causes inflammation

Answer 1

Cellular contents also leak through the damaged plasma membrane into the extra- cellular space, where they elicit a host reaction (inflam- mation).

Bacterial
Fungal
Parasitic 
Viral
Microorganisms 
Microbial toxins
Chemical agents
External injuries 
Inappropriate Immunological responses
Tissue death

Question 2

What is inflammation

Answer 2

The survival of all organisms requires that they eliminate foreign invaders, such as infectious agents, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair. I

Or

General Features of Inflammation
• Inflammation is a defensive host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage.
• The main component

Complex response of vascularized tissue to infections and damaged tissues that brings cells and molecules of host defense from circulation to the site they are needed in order to eliminate the offending agent
Inflammation occurs in tissue that have blood supply
Inflammation is self limiting

Question 3

How does inflammation work

Answer 3

repair. Inflam- mation accomplishes its protective mission by first dilut- ing, destroying, or otherwise neutralizing harmful agents (e.g., microbes, toxins). It then sets into motion the events that eventually heal and repair the sites of injury. Without inflammation, infections would go unchecked and wounds would never heal. In the context of infections, inflamma- tion is one component of a protective response that immu- nologists refer to as innate immunity

Question 4

Importance of inflammation

Answer 4

Although inflammation helps clear infections and other noxious stimuli and initiates repair,

Question 5

The components of the inflammatory reaction
that destroy and eliminate microbes and dead tissues are also capable of injuring normal tissues. Therefore, injury may accompany entirely normal, beneficial inflammatory reactions, and the damage may even become the dominant feature if the reaction is very strong (e.g., when the infec- tion is severe), prolonged (e.g., when the eliciting agent resists eradication), or inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases, or against usually harmless environmental antigens (e.g., in allergic disorders). Some of the most vexing diseases of humans are disorders that result from inappropriate, often chronic, inflammation.
True or false

Answer 5

True

Question 6

What is the goal of inflammation

Answer 6

1. The cells and molecules of host defense, including leukocytes and plasma proteins, normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or tissue damage. To Get rid of the cause of the cell injury
2. In addition, resident cells of vascular walls and the cells and proteins of the extracel- lular matrix (ECM) are also involved in inflammation and repair .get rid of damaged tissues ,necrosed cells .to get rid of consequences of the cell injury

Question 7

Difference between chronic and acute inflammation

And state the important features in acute and chronic inflammation

Define chronic inflammation

Answer 7

Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as hours.and tissue injury is mild and self limiting.local and systemic signs are prominent

1.characterized by fluid and plasma protein exudation and 2.predominantly neutrophilic leukocyte accumulation.
If the acute inflammation is not able to carry its work out the inflammation will lead to chronic inflammation

Chronic inflammation may be more insidious(can start on its own)is of longer duration (days to years), and is typified by influx of lym- phocytes and macrophages with associated vascular pro- liferation and fibrosis (scarring). Tissue injury is often severe and progressive.local and systemic signs are less prominent but may be subtle

Definition of chronic inflammation-Occurs for weeks or months during which these three things occur and they exist in varying combination.

1. Inflammation
2. Tissue injury
3. Attempt at repair

Question 8

How is inflammation induced by chemical mediators

Answer 8

Infections can cause inflammation. Cells in the body have receptors that detect patterns of signals of bacterials or bacterial proteins. When they detect these proteins they open signaling pathways that lead to the production of chemical mediators that will induce inflammation ,autoimmune diseases can also induce inflammation 
Tissue necrosis (uric acid ,foreign bodies (sutures and splinters) when leaked during necrosis causes inflammation)can happen due to ischemia,trauma,hypoxia. 

Inflammation is induced by chemical mediators that are pro- duced by host cells in response to injurious stimuli. When a microbe enters a tissue or the tissue is injured, the presence of the infection or damage is sensed by resident cells, mainly macrophages, but also dendritic cells, mast cells, and other cell types. These cells secrete molecules

(cytokines and other mediators) that induce and regulate the subsequent inflammatory response. Inflammatory mediators are also produced from plasma proteins that react with the microbes or to injured tissues. Some of these mediators promote the efflux of plasma and the recruit- ment of circulating leukocytes to the site where the offend- ing agent is located. The recruited leukocytes are activated and they try to remove the offending agent by phagocyto- sis. An unfortunate side effect of the activation of leuko- cytes may be damage to normal host tissues.

Question 9

What are the five cardinal signs of inflammation,who is the father of modern pathology and also brought the fifth sign and who brought about the first four cardinal signs?

Answer 9

The external manifestations of inflammation, often called its cardinal signs, are
1.heat (calor),
2.redness (rubor),
3.swelling (tumor) (not the same as neoplasia or tumor that is outside inflammation )
4.pain (dolor),
5.loss of function (functio laesa). - pain and swelling resulting in this
The first four of these were described more than 2000 years ago by a Roman encyclopedist named Celsus, who wrote the then- famous text De Medicina, and the fifth was added in the late 19th century by Rudolf Virchow, known as the “father of modern pathology.” These manifestations occur as conse- quences of the vascular changes and leukocyte recruitment and activation

Question 10

How is inflammation self limiting

Answer 10

Inflammation is normally controlled and self-limited. The mediators and cells are activated only in response to the injurious stimulus and are short-lived, and they are degraded or become inactive as the injurious agent is elimi- nated. In addition, various anti-inflammatory mechanisms become active. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation, which can have serious pathologic consequences.

Question 11

What’s re the main components of inflammation ,what are the five steps of inflammatory response and what is the outcome of acute inflammation

Answer 11

The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators derived from plasma proteins and various cells.
• The steps of the inflammatory response can be remem- bered as the five Rs: (1) recognition of the injurious agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of the response, and (5) resolution (repair).
• The outcome of acute inflammation is either elimination of the noxious stimulus, followed by decline of the reac- tion and repair of the damaged tissue, or persistent injury resulting in chronic inflammation.

Question 12

What are the two
Major changes that occur during acute inflammation ,the chemical mediators that cause the smooth muscles to cause vasodilation,and what stimulates it

Answer 12

The acute inflammatory is response rapidly delivers leuko- cytes and plasma proteins to sites of injury. Once there, leukocytes clear the invaders and begin the process of digesting and getting rid of necrotic tissues.
Acute inflammation has two major components
• Vascular changes:1.alterations in vessel caliber resulting in increased blood flow (vasodilation) (earliest sign of acute inflammation) (occurs due to chemical mediators notably histamine and nitric oxide) this leads to opening of new capillary beds causing more blood to rush to the site on injury(causing the redness and the heat) sometimes vasodilation follows a temporary vasoconstriction of the vessels ,alteration in permeability of the vessels follows causing escape of protein rich fluids into the extra vascular space. There will be blood viscosity
Increase cuz of the escape of fluid causing stasis. Stasis causes neutrophils and leukocytes to come to a halt helping them to get out of circulation and migrate to the offending agent
and 2.changes in the vessel wall that permit plasma proteins or protein rich fluid to leave the cir- culation and move into the extravascular tissues(increased vascular permeability ).This causes the red cells in the flowing blood to become more concentrated, thereby increasing blood viscosity and slowing the circulation causing stasis but main cause of stasis is vasodilation. This increased permeability allows plasma proteins and leukocytes to enter sites of infection or tissue damage; fluid leak through blood vessels results in edema.
In addition, endothelial cells are activated, resulting in 3.increased adhesion of leukocytes and migration of the leukocytes through the vessel wall.
•

Cellular events: emigration of the leukocytes from the circulation and accumulation in the focus of injury (cel- lular recruitment), followed by activation of the leuko- cytes, enabling them to eliminate the offending agent. The principal leukocytes in acute inflammation are neu- trophils (polymorphonuclear leukocytes).
Stimuli for Acute Inflammation
Acute inflammatory reactions may be triggered by a variety of stimuli:
• Infections (bacterial, viral, fungal, parasitic) are among the most common and medically important causes of inflammation.
• Trauma (blunt and penetrating) and various physical and chemical agents (e.g., thermal injury, such as burns or frostbite; irradiation; toxicity from certain environ- mental chemicals) injure host cells and elicit inflamma- tory reactions.
• Tissue necrosis (from any cause), including ischemia (as in a myocardial infarct) and physical and chemical injury
• Foreign bodies (splinters, dirt, sutures, crystal deposits)

Immune reactions (also called hypersensitivity reactions) against environmental substances or against “self” tissues. Because the stimuli for these inflammatory responses often cannot be eliminated or avoided, such reactions tend to persist, with features of chronic inflam- mation. The term “immune-mediated inflammatory disease” is sometimes used to refer to this group of disorders.
Although each of these stimuli may induce reactions with some distinctive characteristics, in general, all inflamma- tory reactions have the same basic features.
In this section, we describe first how inflammatory stimuli are recognized by the host, then the typical reac- tions of acute inflammation and its morphologic features, and finally the chemical mediators responsible for these reactions.

Question 13

In granulomatous inflammation what is seen

Answer 13

Foci surrounded by epithelial cells and macrophages

Question 14

Harmful effects of inflammation

Answer 14

If chronic inflammation persists it causes these disease

Rheumatoid arthritis 
Arteriosclerosis 
Lung fibrosis
Autoimmune diseases
Hypersensitivity reaction

Question 15

Major components of inflammation and what happens to them during inflammation ,name the components of blood vessels,in acute or chronic inflammation which leukocytes are dominant in each?

Answer 15

1.Blood vessels(during inflammation blood vessels dilate slowing down blood flow and this is called stasis,alteration in permeability of blood vessels causing leakage of fluid from blood into interstitium or migration of circulatory cells,lymphocytes macrophages to where the injury is

Components or parts of blood vessels -endothelial lining,basement membrane and extra vascular tissue

2.Leukocytes(white blood cell)-
They come to a halt and get out of circulation to migrate to the site of injury
When they’re there they get activated and ingest and destroy the offending agent(microbes ,damaged tissues or foreign bodies)

Acute-polymorphonuclear neutrophils(PMN)leukocytes (Neutrophils, eosinophils, and basophils are PMNs. A PMN is a type of white blood cell. Also called granular leukocyte, granulocyte, and polymorphonuclear leukocyte.)
Chronic inflammation-lymphocytes ,monocytes ,plasma cells

Question 16

What will happen if inflammation does not occur

Answer 16

Wounds won’t heal
Infections won’t be restrained
Injured tissues would remain permanent festering (pus forming sores)

Question 17

What is the hallmark of acute inflammation ?
State the forms of oedema
And define both
What is the amount of specific gravity in exudate

Answer 17

Increased permeability of the microvasculature (the system of tiny blood vessels, including capillaries, venules, and arterioles, that perfuse the body’s tissues.) leading to oedema (2.can be transudate or exudate)

Exudate-Fluid with high specific gravity that’s more than 1.02 and contains high protein concentration and cellular debris)

Transudate-low specific gravity that’s less that 1.02,contains low protein content (mostly albumin ) with no or little cellular materials)

Question 18

State the Major mechanisms that causes increased permeability of microvasculature or increased vascular permeability and explain each as well as
Explain the types of vascular leakage

Answer 18

1. Contraction of endothelial cells-endothelial cells are tightly bound together so when there’s contraction of these cells (by chemical mediators such as bradykinin ,histamine there’s increase in the spaces between the endothelial cells(interendothelial cells) causing leakages of fluid or vascular leakages . The vascular leakage can be very rapid after exposure to the chemical mediators and is short lived usual between 15-30mins(immediate transient response) or delayed prolonged leakage(example burns) usually occurs after 2-12 hours. A slower and more prolonged retraction of endothelial cells, resulting from changes in the cytoskel- eton, may be induced by cytokines such as tumor necro- sis factor (TNF) and interleukin-1 (IL-1). This reaction may take 4 to 6 hours to develop after the initial trigger and persist for 24 hours or more.
2. Endothelial injury-occurs due to direct damage to endothelium (example burns,microorganisms that target endothelial cells directly causing leakage of fluid and neutrophil adherence can also cause damage to endothelium

3.Increased transcytosis - function of vesiculo-vacuolar organelles(acts as channels that allow transport of fluid and proteins thru endothelial cells). They are located close to the endothelial cell junctions.
These organelles can increase in number and size when there’s stimulation of endothelial growth factors(vascular endothelial growth factor (VEGF))Some chemical mediators can stimulate this growth factor causing the increase of the organelles causing more fluids to leak out of the blood vessels

4. Leakage from new blood vessels. As described later, tissue repair involves new blood vessel formation (angiogen- esis). These vessel sprouts remain leaky until prolifer- ating endothelial cells mature sufficiently to form intercellular junctions. New endothelial cells also have increased expression of receptors for vasoactive media- tors, and some of the factors that stimulate angiogenesis (e.g., VEGF) also directly induce increased vascular permeability.

Question 19

Role of ROS in inflammation

Answer 19

Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury.

Question 20

Leukocyte recruitment

Answer 20

Journey of leukcytes from lumen of vessel to the site of inflammation and it occurs right after the vascular event

And the cellular event is basically the leukocytes recruitment
The major leukocytes involved in this are the macrophages and phagocytic cells
When they get to the site of injury the clear up the

When they are strongly activa d they can cause injury to by standing cells

Question 21

1a.Margination alongthe vessel wall,state the characteristics of axial blood flow ,what is axial blood flow
How does the central stream widen

Answer 21

What is the axial blood flow-normal blood flow
Characteristics of axial blood flow
-peripheral cell free layer or peripheral stream(cell free plasma zone)
-central stream made up of the cells(leukocytes and red blood cells)
-platelets

Magination occurs due to stasis and increased vascular permeability and it causes widening of the central stream of cells and plasma zones become narrower due to the plasma loss. Accumulation of leukocytes at the peripheral stream of the vessel is margination

It widens cuz the smaller red cells tend to move faster than the larger white cells, leukocytes are pushed out of the central axial column and thus have a better opportunity to interact with lining endothelial cells, especially as stasis sets in. T

Question 22

b.Rolling along the vessel wall (from magination which is one)
Explain what rolling is,which family of proteins mediate it
Name the three types of proteins in these families and state where they are found
State another name for these types in terms of CD

Answer 22

Rolling is mediated by selectins(a family of
Proteins) which are adhesion molecules. Transient loose attachment and detachment of leukocytes on the epithelial cells. the endothelial cells are activated by cytokines and other mediators produced locally, they express adhesion molecules to which the leukocytes attach loosely. These cells bind and detach and thus begin to tumble on the endothelial surface, a process called rolling

Types of selectins- E selectins (found on surfaced endothelium 
P selectin (found on surface of platelets and endothelium). The P selectin are not normally expressed in the endothelial cells surfaces or platelets in normal conditions but they’re stored in intracellular granules called Weibel-Palable bodies but histamine and thrombin can act on them so they express themselves on the cell surfaces 
L selectin(found on surface of leukocytes )
The leukocytes have ligands which bind to E and P selectin on the surface of the endothelial cells
And on the endothelial cells we have ligands that will bind to the other selectins.

Sialyl -Lewis X modifying glycoprotein on the surface of the leukocyte which bind to E and P selectin on the endothelial surface

On the surface of the endothelium we have glycam 1 or CD 34 which bind to the L selectin on the surface of the leukocyte

When endothelial cells are activated they express the adhesion molecules on their surfaces.

E selectin-CD62E
P selectin-CD62P
L selectin-CD 62L

Question 23

Expression of the different selectins is regulated by different kinds of cytokines and tissue macrophages mast cells and endothelial cells can release lots of cytokines when they encounter microorganisms and dead tissues. True or false
State the cytokines involved in rolling and where they usually act

Answer 23

TNF
Histamine
Thrombin
IL-1

They act on

It takes 1-2hoirs for endothelial cells to express the adhesion molecules on their surfaces

Question 24

2.state what firm Adhesion to the endothelium is mediated by,where they are usually expressed,and what an interaction between integrins and ligands cause
Not all leukocytes are involved in rolling and the ones involved are the ones that’ll be firmly attached to the endothelium leading to their escape from the endothelium true or false

Answer 24

Adhesion is mediated by a family of proteins called integrins (check). They are usually expressed on the surface of leukocyte plasma membrane in the lower affinity stage and their ligands are on the surface of the endothelium.they don’t adhere to their ligands until the leukocytes are activated by chemokines
Beta 1 (example VLA 4)and beta 2 (Mac-1 ,LFA-1) integrins and 

Interaction between the integrins and their ligands under the influence of chemokines will cause leukocytes to be firmly bound to the endothelium

True

Question 25

Beta 2 integrins binds to ICAM-1
Beta 1 integrins will bind to VCAM-1 and all this ensure strong adhesion between the leukocyte and the endothelium
true or false

Answer 25

True

Question 26

How does3. transmigration between cells at intercellular junctions through interendothelial spaces occur and define it

What drives migration of leukocytes and what makes it bind so it can traverse the endothelium

Answer 26

When adhesion occurs rolling leukocytes stop rolling cuz of the strong bonding(adhesion) the leukocytes migrate through the vessel wall by squeezing between cells at intercellular junctions causing transmigration . This extravasation of leukocytes, called diapedesis, occurs mainly in the venules of the systemic vasculature;

Migration of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate movement of the leukocytes toward their chemical gradient.

platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31) makes the binding happen

Escape of leukocytes from the endothelium (transmigration)

Question 27

Another name for PECAM-1
And state the full name of This adhesion molecule
What is it’s function

Answer 27

CD31

Platelet endothelial cell adhesion molecule 1

a cellular adhesion molecule expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium

Question 28

When leukocyte is out of the endothelium it has to move out of the basement membrane
What is secreted to help it do so

Answer 28

After passing through the endothelium, leukocytes secrete

Collagenase help them to get out of the vascular basement membrane

Question 29

What helps leukocytes stay at the site of injury

Answer 29

When leukocytes move to the site of injury They remain there with the help of integrins and CD44

Question 30

Types of chemoattractants and four examples

Answer 30

Endogenous and exogenous

1.Bacterialproducts,particularlypeptideswithN-formyl- methionine termini
• Cytokines, especially those of the chemokine family
• Components of the complement system, particularly C5
• Products of the lipoxygenase pathway of arachidonic
acid (AA) metabolism, particularly leukotriene B4 (LTB4)

Question 31

Mechanism of how chemoatteactants work

What is chemotaxis

(4) migration in inter- stitial tissues toward a chemotactic stimulus or chemotaxis

The direction of movement of the leukocytes is specified by what?

Answer 31

When the chemoaattractant molecules bind to the specific receptors on the leukocyte (G coupled protein receptors),they trigger cytoskeletal contractile elements needed for movement
There’ll be initiation of secondary signaling which causes polymerization of actin at the front and localization of myosin at the back
helping it move to the site of injury

The direction of such movement is specified by a higher density of chemokine receptors at the leading edge of the cell. Thus, leukocytes move to and are retained at the site where they are needed

After extravasating from the blood, leuko- cytes move toward sites of infection or injury along a chem- ical gradient by a process called chemotaxis.

Question 32

When they get to the site of injury the leukocytes will be activated and engulf and kill the infective agent or offending agent
True or false

Some of these receptors recognize components of the microbes and dead cells and other receptors recognize host proteins
True or false

State the three Mechanism of phagocytosis
And name the types of receptors used in recognition and attachment
Name the host proteins that coat microbes and target them for phagocytosis and what are the two the most important type of these host products

Answer 32

True
True

Recognition and attachment of the particle to the ingesting leukocyte -done with the help of receptors.
Killing and Degradation

Engulfment

Killing and degradation of ingest material

opsonins, The most important opsonins are antibodies of the immunoglobulin G (IgG) class and plasma carbohydrate-binding lectins called col- lectins

Leu- kocytes express receptors for opsonins that facilitate rapid phagocytosis of the coated microbes. These receptors include the Fc receptor for IgG (called FcγRI), complement receptors 1 and 3 (CR1 and CR3) for complement frag- ments, and C1q for the collectins.

Question 33

Pinocytosis

Major cells that do the phagocytosis thing

Answer 33

Engulfment of liquid particles

Macrophages and neutrophil (PMn or something)

Question 34

Phagosome fuses with lysosome to form

Answer 34

Phagolysosome

Question 35

Name five growth receptors ,their growth factors,sources and functions

Answer 35

Epidermal growth factor (EGF) - epidermal growth factor receptor
Sources:Activated macrophages, salivary glands
Functions:Mitogenic for keratinocytes and
fibroblasts; stimulates keratinocytes, and many other cells keratinocyte migration; stimulates formation of
granulation tissue

Keratinocyte growth factor (KGF) (FGF-7)
Sources:Fibroblasts
Functions:Stimulates keratinocyte migration, proliferation, and (i.e., FGF-7) differentiation

Hepatocyte growth factor (HGF) (scatter factor)
Sources:Fibroblasts, stromal cells in the liver, functions:Enhances proliferation of hepatocytes and other factor) endothelial cells epithelial cells; increases cell motility

Transforming growth factor-α (TGF-α) sources:Activated macrophages, keratinocytes,
Functions:Stimulates proliferation of hepatocytes and many many other cell types other epithelial cells

Vascular endothelial growth factor (VEGF) -VEGF receptor
Sources:Mesenchymal cells
Functions:Stimulates proliferation of endothelial cells; increases vascular permeability

Platelet-derived growth factor (PDGF) - PDGF receptor
Sources:Platelets, macrophages, endothelial cells,
Functions:Chemotactic for neutrophils, macrophages, fibroblasts, smooth muscle cells, keratinocytes and smooth muscle cells; activates and stimulates
proliferation of fibroblasts, endothelial, and other cells; stimulates ECM protein synthesis

Fibroblast growth factors (FGFs), including acidic FGF-1 and basic FGF-2 receptor: FGF receptor
Sources:Macrophages, mast cells, endothelial cells,
Functions :Chemotactic and mitogenic for fibroblasts; stimulates acidic (FGF-1) and basic (FGF-2) many other cell types angiogenesis and ECM protein synthesis

Transforming growth factor-β (TGF-β) sources:Platelets, T lymphocytes, macrophages
Functions:Chemotactic for leukocytes and fibroblasts; stimulates endothelial cells, keratinocytes, smooth ECM protein synthesis; suppresses acute inflammation
muscle cells, fibroblasts

Question 36

Name four causes of diseases

Answer 36

agents, toxins, mutagens, drugs, allergens, trauma, or genetic mutations).

Question 37

What will cause the pain and swelling as well as loss of function in inflammation

Answer 37

chemicals including histamine, bradykinin, and prostaglandins. These chemicals cause blood vessels to leak fluid into the tissues, causing swelling.

inflammation typically causes pain because the swelling and buildup of tissue starts pressing against nerve endings. This pressure sends pain signals to the brain, causing discomfort.

Loss of function may result from pain that inhibits mobility or from severe swelling that prevents movement in the area.

Question 38

Function and sources of cell derived mediators of inflammation such as histamine ,serotonin,leukotrienes,platelet activating factor,ROS,nitric oxide,cytokines,Chemokines and prostaglandin and plasma protein derived mediators of inflammation (complement,kin in,professes activated during coagulation)

Answer 38

Classic endogenous mediators such as prostaglandins and leukotrienes dilate vasculatures, enhance permeability of capillaries, increase blood flow, and stimulate the recruitment of neutrophils (PMNs) to form inflammatory exudate.

Histamine- Mast cells, basophils, platelets functions-Vasodilation, increased vascular permeability, endothelial activation, histamine causes arteriolar dilation and rapidly increases vascular permeability by inducing venular endothelial contrac- tion and formation of interendothelial gaps. Soon after its release, histamine is inactivated by histaminase
Serotonin -Platelets(released during platelet aggregation)
function-Vasoconstriction
Prostaglandins -Mast cells, leukocytes function-Vasodilation, pain, fever
Leukotrienes -Mast cells, leukocytes functions-Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
Platelet-activating factor -Leukocytes, mast cells
Functions-Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Reactive oxygen species -Leukocytes functions -Killing of microbes, tissue damage
Nitric oxide -Endothelium, macrophages functions-Vascular smooth muscle relaxation; killing of microbes, important function of NO is as a microbicidal (cyto- toxic) agent in activated macrophages. NO plays other roles in inflammation, including vasodilation, antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation), and reduction of leukocyte recruit- ment at inflammatory sites.
Cytokines (TNF, IL-1, IL-6) -Macrophages, endothelial cells, mast cells Local: endothelial activation (expression of adhesion molecules).
Systemic: fever, metabolic abnormalities, hypotension (shock)
Chemokines -Leukocytes, activated macrophages
Chemotaxis, leukocyte activation

Plasma Protein–Derived
Complement -Plasma (produced in liver) functions-Leukocyte chemotaxis and activation, direct target killing (MAC), vasodilation (mast cell stimulation)
Kinins -Plasma (produced in liver) functions-Increased vascular permeability, smooth muscle contraction, vasodilation, pain
Proteases activated during coagulation-Plasma (produced in liver)
Functions-Endothelial activation, leukocyte recruitment

Question 39

Function of TNF
What are the major cytokines in acute inflammation and where are they produced,what stimulates their secretion,what are their principal roles

TNF also increases the throm- bogenicity of endothelium. IL-1 activates tissue fibroblasts, resulting in increased proliferation and production of ECM. True or false

Although TNF and IL-1 are secreted by macrophages and other cells at sites of inflammation, they may enter the circulation and act at distant sites to induce the systemic acute-phase reaction that is often associated with infection and inflammatory diseases. Components of this reaction include fever, lethargy, hepatic synthesis of various acute- phase proteins (also stimulated by IL-6), metabolic wasting (cachexia), neutrophil release into the circulation, and fall in blood pressure
True or false

What are the three main functions of chemokines
At higher levels state three things ROS does to cause injury

The potentially damaging effects of lysosomal enzymes are limited by antiproteases present in the plasma and tissue fluids. These include α1-antitrypsin, the major inhibi- tor of neutrophil elastase, and α2-macroglobulin. Deficien- cies of these inhibitors may result in sustained activation of leukocyte proteases, resulting in tissue destruction at sites of leukocyte accumulation. For instance, α1-antitrypsin deficiency in the lung can cause a severe panacinar emphysema. True or false

Answer 39

TNF-α participates in vasodilatation and edema formation, and leukocyte adhesion to epithelium through expression of adhesion molecules; it regulates blood coagulation, contributes to oxidative stress in sites of inflammation, and indirectly induces fever.1

TNF,IL-1,IL-6 and chemokines which are a group of chemoattractant cytokines

1TNF and IL-1 are produced by activated macrophages, as well as mast cells, endothelial cells, and some other cell types (Fig. 2–17).

Their secretion is stimulated by microbial products, such
as bacterial endotoxin, immune complexes, and products of T lymphocytes generated during adaptive immune responses.

The principal role of these cytokines in inflammation is in endothelial activation. Both TNF and IL-1 stimulate the expression of adhesion molecules on endothelial cells, resulting in increased leukocyte binding and recruitment, and enhance the production of additional cytokines (notably chemo- kines) and eicosanoids.
. These systemic manifestations of inflam- mation are described later in the chapter.

The two main functions of chemokines are to recruit leukocytes to the site of inflammation and to control the normal ana- tomic organization of cells in lymphoid and other tissues.
Chemokines also activate leuko- cytes; one consequence of such activation, is increased affinity of leukocyte integrins for their ligands on endothelial cells.

When secreted at low levels, ROS can increase chemokine, cytokine, and adhe- sion molecule expression, thus amplifying the cascade of inflammatory mediators. At higher levels, these mediators are responsible for tissue injury by several mechanisms, including (1) endothelial damage, with thrombosis and increased permeability; (2) protease activation and antipro- tease inactivation, with a net increase in breakdown of the ECM; and (3) direct injury to other cell types (e.g., tumor cells, red cells, parenchymal cells).

Question 40

phagocytes, dendritic cells (cells in connective tissue and organs that capture microbes and initiate responses to them), and many other cells, such as epithelial cells, express receptors that are designed to sense the presence of infectious pathogens and substances released from dead cells. True or false
What is the name of those receptors and state the two most important families of those receptors
How many mammalian TLRs are there
Where are the found mainly
What are they complemented by

Answer 40

These recep- tors have been called “pattern recognition receptors” because they recognize structures (i.e., molecular patterns) that are common to many microbes or to dead cells. The two most important families of these receptors are the following:
1.• Toll-like receptors (TLRs) are microbial sensors that are named for the founding member called Toll, which was discovered in Drosophila. There are ten mammalian TLRs, which recognize products of bacteria (such as
endotoxin and bacterial DNA), viruses (such as double- stranded RNA), and other pathogens
TLRs are located in plasma membranes and endosomes, so they are able to detect extracellular and ingested microbes.
They are complemented by cytoplasmic and membrane molecules, from several other families, that also recognize microbial products. TLRs and the other receptors recognize products of different types of microbes and thus provide defense against essentially all classes of infectious pathogens.

2.The inflammasome is a multi-proteincytoplasmiccomplex that recognizes products of dead cells, such as uric acid and extracellular ATP, as well as crystals and some microbial products.

Question 41

How do TLRs work and what happens when inflammasomes are activated

Answer 41

Recognition of microbes by these receptors activates transcription factors that stimulate the production of a number of secreted and membrane proteins. These proteins include mediators of inflammation, antiviral cytokines (interfer- ons), and proteins that promote lymphocyte activation and even more potent immune responses. We return to TLRs in Chapter 4, when we discuss innate immunity

Triggering of the inflammasome results in activation of an enzyme called caspase-1, which cleaves precursor forms of the inflammatory cytokine interleukin-1β (IL-1β) into its biologically active form

B, The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin-1 (IL-1). The inflammasome consists of a sensor protein (a leucine-rich protein called NLRP3), an adaptor, and the enzyme caspase-1, which is converted from an inactive to an active form.

Question 42

Importance of IL-1

The joint disease, gout, is caused by deposition of urate crystals, which are ingested by phagocytes and activate the inflammasome, resulting in IL-1 production and acute inflammation. IL-1 antago- nists are effective treatments in cases of gout that are resistant to conventional anti-inflammatory therapy.
True or false

Answer 42

IL-1 is an impor- tant mediator of leukocyte recruitment in the acute inflammatory response, and the leukocytes phagocytose and destroy dead cells.
True

Question 43

Exudates must be distinguished from transudates, which are interstitial fluid accumulations caused by increased hydrostatic pres- sure, usually a consequence of reduced venous return. . Whereas exudates are typical of inflammation, transudates accumulate in various nonin- flammatory conditions.
True or false

Answer 43

True

Question 44

State the difference between lymphadenitis and lymphangitis

What signs are a constellation of pathologic changes called reactive lymphadenitis ?

lymphatic vessels also partici- pate in the inflammatory response. In inflammation, lymph flow is increased and helps drain edema fluid, leukocytes, and cell debris from the extravascular space. In severe inflammatory reactions, especially to microbes, the lym- phatics may transport the offending agent, contributing to its dissemination true or false
True

For clinicians, what is a telltale sign of an infec- tion in the wound

Answer 44

The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).

Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and phagocytic cells lining the sinuses of the lymph nodes. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis (Chapter 11).

For clinicians, the presence of red streaks near a skin wound is a telltale sign of an infec- tion in the wound. This streaking follows the course of the lymphatic channels and is diagnostic of lymphangitis; it may be accompanied by painful enlargement of the drain- ing lymph nodes, indicating lymphadenitis.

Question 45

A price that is paid for the defensive potency of leukocytes is that once activated, they may induce tissue damage and prolong inflammation, since the leukocyte products that destroy microbes can also injure normal host tissues. Therefore, host defense mecha- nisms include checks and balances that ensure that leuko- cytes are recruited and activated only when and where they are needed (i.e., in response to foreign invaders and dead tissues). Systemic activation of leukocytes can, in fact, have detrimental consequences, as in septic shock
True or false

Answer 45

True

Question 46

Leukocyte Recruitment
Leukocytes normally flow rapidly in the blood, and in inflamma- tion, they have to be stopped and brought to the offending agent or the site of tissue damage, which are typically outside the vessels.
True or false

Answer 46

True

Question 47

The endothelial selectins are typically expressed at low levels or are not present at all on unactivated endothelium, and are up-regulated after stimulation by cytokines and other mediators. Therefore, binding of leukocytes is largely restricted to endothelium at sites of infection or tissue injury (where the mediators are produced). For example, in unactivated endothelial cells, P-selectin is found primar- ily in intracellular Weibel-Palade bodies; however, within minutes of exposure to mediators such as histamine or thrombin, P-selectin is distributed to the cell surface, where it can facilitate leukocyte binding. Similarly, E-selectin and the ligand for L-selectin, which are not expressed on normal endothelium, are induced after stimulation by the cyto- kines IL-1 and TNF
True or false

Answer 47

True

Question 48

What is the role and which leukocyte molecule binds to P selectin, E selectin , Glycam-1 or CD34,ICAM-1,VCAM-1,CD-31

What is the role of LFA-1 and where is it found

Answer 48

P selectin- Sialyl -Lewis Xmodified protein
Role-Rolling

E selectin-Sialyl-Lewis X modified protein
Role -Rolling and adhesion

GlyCam1- L selectin
Role-Rolling(neutrophils and monocytes)

ICAM(CD54)-CD11,CD18, integrins LFA-1 and Mac-1
Role-firm adhesion,arrest and transmigration

VCAM- VLA-4integrin
Role-Adhesion

CD31-CD31
Role- transmigration of leukocytes through the endothelium

Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes.

Question 49

What are chemokines and ,where are they displayed,where are they secreted at
What happens (to integrins )when adherent leukocytes encounter displayed chemokines
While this is happening what is happening to other cytokines

Name the ligands and the integrins they bind to
State the full meaning of MAc-1,LFA-1 and VLA-4

Answer 49

Chemokines are chemoattractant cytokines that are secreted by many cells at sites of inflammation and are displayed on the endothelial surface.

When the adherent leuko- cytes encounter the displayed chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, thus converting to a high- affinity form. At the same time, other cytokines, notably TNF and IL-1 (also secreted at sites of infection and injury), activate endothelial cells to increase their expression of ligands for integrins.

These ligands include intercellular adhesion molecule-1 (ICAM-1), which binds to the integ- rins leukocyte function–associated antigen-1 (LFA-1) (also called CD11a/CD18) and macrophage-1 antigen (Mac-1) (i.e., CD11b/CD18), and vascular cell adhesion molecule-1 (VCAM-1), which binds to the integrin very late antigen-4 (VLA-4)

Question 50

The type of emigrating leukocyte varies with the age of the inflammatory response and with the type of stimulus. In most forms of acute inflammation, neutrophils predomi- nate (cuz they bind better,are abundant and respond more rapidly to chemokines)in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours
True or false

Answer 50

True

Question 51

Once leukocytes have been recruited to the site of infection or tissue necrosis, they must be activated to perform their functions. Stimuli for activation include microbes, products of necrotic cells, and several mediators that are described later. As described earlier, leukocytes use various receptors to sense the presence of microbes, dead cells, and
foreign substances. True or false

Leukocyte activation results in the enhancement of four functions name then:

Answer 51

1.Phagocytosis of particles
• Intracellular destruction of phagocytosed microbes and deadcells by substances produced in phagosomes, including reactive oxygen and nitrogen species and lysosomal enzymes
• Liberation of substances that destroy extracellular microbes and dead tissues, which are largely the same as the sub- stances produced within phagocytic vesicles.
• Production of mediators, including arachidonic acid metabolites and cytokines, that amplify the inflamma- tory reaction, by recruiting and activating more leukocytes

Question 52

opsonins either are present in the blood ready to coat
microbes or are produced in response to the microbes. True or false

State the functions of opsonin and functions of the types of opsonins

When opsonized particles bind to the receptors on the leukocytes what happens

Answer 52

True

coat microbes and target them for phagocytosis (the process called opsonization).

IgG-bind to microbial surface antigens
Collectins-which bind to microbial cell wall sugar groups.

Binding of opsonized particles to these receptors trig- gers engulfment and induces cellular activation that enhances degradation of ingested microbes. In engulfment, pseudopods are extended around the object, eventually forming a phagocytic vacuole. The membrane of the vacuole then fuses with the membrane of a lysosomal granule, resulting in discharge of the granule’s contents into the phagolysosome.

Question 53

What are the key steps in killing and degradation of phagocytosed molecules

How is ROS produced as a microbicidal substance in the lysosome

Answer 53

The key steps in this reaction are the production of microbicidal substances within lysosomes and fusion of the lysosomes with phago- somes, thus exposing the ingested particles to the destruc- tive mechanisms of the leukocytes .

Phagocytosis and the engagement of various cellular receptors stimulate an oxidative burst, also called the respiratory burst (which is characterized by a rapid increase in oxygen consumption, glycogen catabolism (glycogenolysis), increased glucose oxidation, and production of ROS)
The generation of the oxygen
metabolites is due to rapid activation of a leukocyte NADPH oxidase, called the phagocyte oxidase, which oxi- dizes NADPH (reduced nicotinamide adenine dinucleo- tide phosphate) and, in the process, converts oxygen to superoxide ion (O2• )
• Superoxide is then converted by spontaneous dismuta- tion into hydrogen peroxide (O2• + 2H+ → H2O2). These ROS act as free radicals and destroy microbes
• The quantities of H2O2 produced generally are insuffi- cient to kill most bacteria (although superoxide and hydroxyl radical formation may be sufficient to do so). However, the lysosomes of neutrophils (called azuro- philic granules) contain the enzyme myeloperoxidase (MPO), and in the presence of a halide such as Cl−, MPO converts H2O2 to HOCl• (hypochlorous radical). HOCl• is a powerful oxidant and antimicrobial agent (NaOCl is the active ingredient in chlorine bleach) that kills bacteria by halogenation, or by protein and lipid peroxidation.

Question 54

the phagocyte oxidase is active only after its cytosolic subunit translocates to the membrane of the pha- golysosome; thus, the reactive end products are generated mainly within the vesicles, and the phagocyte itself is not damaged. H2O2 is eventually broken down to water and O2 by the actions of catalase, and the other ROS also are degraded (Chapter 1). Reactive nitrogen species, particu- larly nitric oxide (NO), act in the same way as that described for ROS. The dead microorganisms are then degraded by the action of lysosomal acid hydrolases. Perhaps the most important lysosomal enzyme involved in bacterial killing is elastas
True or false

Answer 54

True

Question 55

Name five components of the leukocyte granules or phagolysosomes
State the function of elastase

Answer 55

ROS
Lysosomal enzymes
bactericidal permeability-increasing protein (causing phospholipase activation and membrane phospholipid degradation),
lyso- zyme (causing degradation of bacterial coat oligosaccha- rides),
major basic protein (an important eosinophil granule constituent that is cytotoxic for parasites), and
defensins (peptides that kill microbes by creating holes in their membranes).

The microbicidal mechanisms of phagocytes are largely sequestered within phagolysosomes in order to protect the leukocytes from damaging themselves. Leukocytes also actively secrete granule components including enzymes such as elastase, which destroy and digest extracellular microbes and dead tissues, as well as antimicrobial peptides.

Question 56

What are NeTs and how d they cause death of neutrophils

Answer 56

Neutrophil Extracellular Traps (NETs). These “traps” are extracellular fibrillar networks that are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (such as chemokines, cytokines, complement proteins, and ROS). NETs contain a framework of nuclear chromatin with embedded granule proteins, such as antimicrobial peptides and enzymes (Fig. 2–9). The traps provide a high concen- tration of antimicrobial substances at sites of infection, and prevent the spread of the microbes by trapping them in the fibrils. In the process, the nuclei of the neutrophils are lost, leading to death of the cells. NETs also have been detected in blood neutrophils during sepsis.

Question 57

Name three ways in which leukocytes cause injury and give three examples of leukocyte induced injury both acute and chronic

Answer 57

As part of a normal defense reaction against infectious microbes, when “bystander” tissues are injured. In certain infections that are difficult to eradicate, such as tuberculosis and some viral diseases, the host response more to the pathological process than does the microbe itself

• As a normal attempt to clear damaged and dead tissues
(e.g., after a myocardial infarction). In an infarct, inflam- mation may prolong and exacerbate the injurious con- sequences of the ischemia, especially upon reperfusion (Chapter 1).
• When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases, or when the host reacts excessively against nontoxic environmental substances, such as allergic dis- eases including asthma

Acute
Asthma-Eosinophils;IgE antibodies
Septic shock-cytokines
Glomerulonephritis-neutrophils,monocytes,antibodies and complement
Acute transplant rejection -lymphocytes,antibodies and complement

Chronic-
Asthma-same as in acute
Rheumatoid arthritis-lymphocytes,macrophages,antibodies
Pulmonary fibrosis-fibroblasts,macrophages
Chronic transplant rejection-lymphocytes,macrophages,cytokines

Question 58

Defects in leukocyte functions can cause increased susceptibility true or false
What three most common causes of defective inflammation
Name and explainthree genetic disorders of leukocyte functions

Answer 58

True

he most common causes of defective inflammation are bone marrow suppression caused by tumors or treatment with chemotherapy or radiation and leukemia resulting in decreased leukocyte numbers) and metabolic diseases such as diabetes (causing abnormal leukocyte functions by affecting leukocyte adhesion)
The genetic disorders;
• Defects in leukocyte adhesion. In leukocyte adhesion defi- ciency type 1 (LAD-1), defective synthesis of the CD18 β subunit of the leukocyte integrins LFA-1 and Mac-1 leads to impaired leukocyte adhesion to and migration through endothelium, and defective phagocytosis and generation of an oxidative burst.

Leukocyte adhesion defi- ciency type 2 (LAD-2) is caused by a defect in fucosyl metabolism resulting in the absence of sialyl–Lewis X, Its clinical manifestations are similar to but milder than those of LAD-1.
•
Defects in microbicidal activity.An example is chronic granulomatous disease, a genetic deficiency in one of the several components of the phagocyte oxidase enzyme that is responsible for generating ROS. In these patients, engulfment of bacteria does not result in activation of oxygen-dependent killing mechanisms. In an attempt to control these infections, the microbes are surrounded by activated macrophages, forming the “granulomas” (see later) that give the disease its distinctive pathologic fea- tures and its somewhat misleading name.
• Defects in phagolysosome formation. One such disorder, Chédiak-Higashi syndrome, is an autosomal recessive disease that results from disordered intracellular traf- ficking of organelles, ultimately impairing the fusion of lysosomes with phagosomes. The secretion of lytic secretory granules by cytotoxic T lymphocytes is also
H2O2, hydrogen peroxide; MPO, myeloperoxidase.

• Rare patients with defective host defenses have been
shown to carry mutations in TLR signaling pathways. Inherited defects in components of adaptive immune responses also result in increased susceptibility to infec- tions.
• Gain-of-function mutations in genes encoding some compo- nents of the inflammasome, one of which is called cryo- pyrin, are responsible for rare but serious diseases called cryopyrin-associated periodic fever syndromes (CAPSs), which manifest with unrelenting fevers and other signs of inflammation and respond well to treatment with IL-1 antagonists.

Acquired
Bone marrow suppression: Production of leukocytes tumors (including leukemias),
radiation, and chemotherapy
Diabetes, malignancy, sepsis, Adhesion and chemotaxis chronic dialysis
Anemia, sepsis, diabetes, Phagocytosis and microbicidal activity malnutrition
Genetic
Leukocyte adhesion: Defective leukocyte adhesion because deficiency 1 of mutations in β chain of CD11/
CD18 integrins
Leukocyte adhesion Defective leukocyte adhesion because deficiency 2 of mutations in fucosyl transferase required for synthesis of sialylated
oligosaccharide (receptor for selectins)
Chronic granulomatous Decreased oxidative burst disease
X-linked Phagocyte oxidase (membrane component)
Autosomal recessive Phagocyte oxidase (cytoplasmic components)
Myeloperoxidase deficiency Decreased microbial killing because of defective MPO–H2O2 system
Chédiak-Higashi syndrome Decreased leukocyte functions because of mutations affecting protein invol

Question 59

What are the three outcomes of acute inflammation
And state the difference between regeneration and repair
What is scarring?

In organs in which extensive connec- tive tissue deposition occurs in attempts to heal the damage or as a consequence of chronic inflammation, the outcome is fibrosis, which is a process that can compromise function true or false

Answer 59

acute inflammation generally has one of three out- comes (Fig. 2–10):
• Resolution: Regeneration and repair. When the injury is limited or short-lived, when there has been no or minimal tissue damage, and when the injured tissue is capable of regenerating, the usual outcome is restoration to structural and functional normalcy.
• Chronic inflammation may follow acute inflammation if the offending agent is not removed, or it may be present from the onset of injury (e.g., in viral infections or immune responses to self-antigens). Depending on the extent of the initial and continuing tissue injury, as well as the capacity of the affected tissues to regrow, chronic inflammation may be followed by restoration of normal structure and function or may lead to scarring.
• Scarring is a type of repair after substantial tissue destruction (as in abscess formation, discussed later) or when inflammation occurs in tissues that do not
regenerate, in which the injured tissue is filled in by connective tissue.

Regeneration-healing occurs by proliferation of parenchymal cells and tissues (these cells are responsible for organ function)and there is almost complete restoration of damaged cells. Human regeneration is not true regeneration cuz the structure won’t be regenerated it’s the functions that will be compensated for while repair is proliferation of connective or supporting tissue leading to fibrosis and scar formation

Question 60

What does termination of acute response include

Answer 60

Before the process of resolution can start, the acute inflammatory response has to be terminated. This involves neutralization, decay, or enzymatic degradation of the various chemical medi- ators; normalization of vascular permeability; and ces- sation of leukocyte emigration, with subsequent death (by apoptosis) of extravasated neutrophils. Furthermore, leukocytes begin to produce mediators that inhibit inflammation, thereby limiting the reaction. The necrotic debris, edema fluid, and inflammatory cells are cleared by phagocytes and lymphatic drainage, eliminating the detritus from the battlefield.

Leukocytes secrete cytokines that initiate the subsequent repair process, in which new blood vessels grow into the injured tissue to provide nutrients, growth factors stimulate the prolif- eration of fibroblasts and laying down of collagen to fill defects, and residual tissue cells proliferate to restore structural integrity.

Question 61

The severity of the inflammatory response, its specific cause, and the particular tissue involved all can modify the basic morphology of acute inflammation, pro- ducing distinctive appearances. The importance of recog- nizing these morphologic patterns is that they are often associated with different etiology and clinical situations.
True or false
State the four morphological patterns of acute inflammation and explain with examples
What is an effusion?

A fibrous exudate is characteristic in lining of which body cavities?
When extensive fibrin rich exudates are not completely removed what are they replaced by?
What are abscesses

What is an ulcer ,ulcers are mostly encountered where?
When can ulceration only occur? And give an example

Answer 61

• Serous inflammation is characterized by the outpour- ing of a watery, relatively protein-poor fluid that, depend- ing on the site of injury, derives either from the plasma or from the secretions of mesothelial cells lining the perito- neal, pleural, and pericardial cavities.
The skin blister resulting from a burn or viral infection is a good example of the accumulation of a serous effusion either within or immediately beneath the epidermis of the skin .Fluid in a serous cavity is called an effusion.
•
Fibrinous inflammation occurs as a consequence of more severe injuries, resulting in greater vascular perme- ability that allows large molecules (such as fibrinogen) to pass the endothelial barrier. Histologically, the accumu- lated extravascular fibrin appears as an eosinophilic mesh- work of threads or sometimes as an amorphous coagulum
A fibrinous exudate is characteristic of inflam- mation in the lining of body cavities, such as the meninges, pericardium, and pleura.
Such exudates may be degraded by fibrinolysis, and the accumulated debris may be removed by macrophages, resulting in restoration of the normal tissue structure (resolution). However, exten- sive fibrin-rich exudates may not be completely removed, and are replaced by an ingrowth of fibroblasts and blood vessels (organization), leading ultimately to scar- ring that may have significant clinical consequences. For
example, organization of a fibrinous pericardial exudate forms dense fibrous scar tissue that bridges or obliterates the pericardial space and restricts myocardial function.
• Suppurative (purulent) inflammation and abscess formation. These are manifested by the collection of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid.

Certain organ- isms (e.g., staphylococci) are more likely to induce such localized suppuration and are therefore referred to as pyogenic (pus-forming). Abscesses are focal collections of pus that may be caused by seeding of pyogenic organ- isms into a tissue or by secondary infections of necrotic foci. Abscesses typically have a central, largely necrotic region rimmed by a layer of preserved neutrophils with a surrounding zone of dilated vessels and fibroblast proliferation indicative of attempted repair.As time passes, the abscess may become completely walled off and eventually be replaced by connective tissue. Because of the underlying tissue destruction, the usual outcome with abscess formation is scarring.

• An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of necrotic and inflammatory tissue .Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a
surface. Ulcers are most commonly encountered in (1) the mucosa of the mouth, stomach, intestines, or genito- urinary tract and (2) in the subcutaneous tissues of the lower extremities in older persons who have circulatory disturbances predisposing affected tissue to extensive necrosis. Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist.

Question 62

Name three characteristics of chemical

Mediators

Answer 62

Mediators may be produced locally by cells at the site of inflammation, or may be derived from circulating inactive precursors (typically synthesized by the liver) that are acti- vated at the site of inflammation .Cell-derived mediators are normally sequestered in intracellular granules and are rapidly secreted upon cel- lular activation (e.g., histamine in mast cells) or are synthesized de novo in response to a stimulus (e.g., prostaglandins and cytokines produced by leukocytes and other cells). Plasma protein–derived mediators (complement proteins, kinins) circulate in an inactive form and typically undergo proteolytic cleavage to acquire their biologic activities.
• Most mediators act by binding to specific receptors on differ- ent target cells. Such mediators may act on only one or a very few cell types, or they may have diverse actions,
Table 2–5 Actions of the Principal Mediators of Inflammation
with differing outcomes depending on which cell type they affect. Other mediators (e.g., lysosomal proteases, ROS) have direct enzymatic and/or toxic activities that do not require binding to specific receptors.
• Theactionsofmostmediatorsaretightlyregulatedandshort- lived. Once activated and released from the cell, media- tors quickly decay (e.g., arachidonic acid metabolites), are inactivated by enzymes (e.g., kininase inactivates bradykinin), are eliminated (e.g., antioxidants scavenge toxic oxygen metabolites), or are inhibited (e.g., complement regulatory proteins block complement activation).
Cell-Derived

Question 63

Name the two vasoactive amines that are cell derived mediators,name the four arachidonic acid metabolites (Eiconasoids)that are cell derived mediators

AA is a 20-carbon polyunsaturated fatty acid (with four double bonds)
True or false

The prostaglandins also contribute to the pain and fever that accompany inflammation; PGE2 aug- ments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever.
• Leukotrienes. Leukotrienes are produced by the action of 5-lipoxygenase, the major AA-metabolizing enzyme in neutrophils. The synthesis of leukotrienes involves mul- tiple steps .are pro- duced mainly in mast cells and cause bronchoconstric- tion and increased vascular permeability.
• Lipoxins. Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhe- sion to endothelium and thus serve as endogenous antagonists of leukotrienes. Platelets that are activated and adherent to leukocytes also are important sources of lipoxins.
True or false

Answer 63

Histamine
Serotonin  (5-hydroxytryptamine) It induces vasoconstriction during clotting. It is produced mainly in some neurons and enterochromaffin cells, and is a neurotransmitter and regulates intestinal motility.

AA metabolism proceeds along one of two major enzymatic pathways: Cyclooxygen- ase stimulates the synthesis of prostaglandins and throm- boxanes, and lipoxygenase is responsible for production of leukotrienes and lipoxins

Question 64

Histamine is released in response to many stimuli name them

Name the functions of platelet activating factor 1

Answer 64

Preformed histamine is released from mast cell granules in response to a variety of stimuli: (1) physical injury such as trauma or heat; (2) immune reactions involving binding of IgE antibodies to Fc receptors on mast cells (Chapter 4); (3) C3a and C5a fragments of complement, the so-called anaphylatoxins (see later); (4) leukocyte-derived histamine-releasing proteins; (5) neuropeptides (e.g., substance P); and (6) certain cytokines (e.g., IL-1, IL-8).

PAF-In addi- tion to stimulating platelets, PAF causes bronchoconstric- tion and is 100 to 1000 times more potent than histamine in inducing vasodilation and increased vascular permeabil- ity. It also stimulates the synthesis of other mediators, such as eicosanoids and cytokines, from platelets and other cells. Thus, PAF can elicit many of the reactions of inflammation,
including enhanced leukocyte adhesion, chemotaxis, leu- kocyte degranulation, and the respiratory burst.

Question 65

What do complement proteins do when activated
Name four phenomena complement proteins contribute to in acute inflammation

The activation of complement is tightly controlled by cell- associated and circulating regulatory proteins. The presence of these inhibitors in host cell membranes protects normal cells from inappropriate damage during protective reac- tions against microbes. Inherited deficiencies of these regulatory proteins lead to spontaneous complement activation:
True or false

Kininsystemactivationleadsultimatelytotheformation of bradykinin from its circulating precursor, high- molecular-weight kininogen (HMWK) (Fig. 2–19). Like histamine, bradykinin causes increased vascular perme- ability, arteriolar dilation, and bronchial smooth muscle contraction. I
True or false

Which mediators cause the fever and tissue damage

Kinins: Produced by proteolytic cleavage of precursors, this group mediates vascular reaction and pain.true or false

Answer 65

Upon activation, different complement proteins
coat (opsonize) particles, such as microbes, for phagocyto- sis and destruction, and contribute to the inflammatory response by increasing vascular permeability and leuko- cyte chemotaxis.

Vascular effects. C3a and C5a increase vascular permea- bility and cause vasodilation by inducing mast cells to release histamine. These complement products are also called anaphylatoxins because their actions mimic those of mast cells, which are the main cellular effectors of the severe allergic reaction called anaphylaxis (Chapter 4). C5a also activates the lipoxygenase pathway of AA metabolism in neutrophils and macrophages, causing release of more inflammatory mediators.
• Leukocyte activation, adhesion, and chemotaxis. C5a, and to lesser extent, C3a and C4a, activate leukocytes, increas- ing their adhesion to endothelium, and is a potent che- motactic agent for neutrophils, monocytes, eosinophils, and basophils.
• Phagocytosis. When fixed to a microbial surface, C3b and its inactive proteolytic product iC3b act as opsonins, augmenting phagocytosis by neutrophils and macro- phages, which express receptors for these complement products.
• The MAC, which is made up of multiple copies of the final component C9, kills some bacteria (especially thin- walled Neisseria) by creating pores that disrupt osmotic balance.

IL-1, TNF Prostaglandins

Tissue damage -Lysosomal enzymes of leukocytes Reactive oxygen species
Nitric oxide

Question 66

Name three anti inflammatory mechanism

Answer 66

Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhe- sion to endothelium and thus serve as endogenous antagonists of leukotrienes. Platelets that are activated and adherent to leukocytes also are important sources of lipoxins.

Some of these, such as lipoxins, and complement regulatory proteins, have been mentioned earlier.

-Activated macrophages and other cells secrete a cytokine, IL-10, whose major function is to down-regulate the responses of activated macrophages, thus providing a negative feedback loop.

Cells also express a number of intracellular proteins, such as tyrosine phosphatases, that inhibit pro-inflammatory
signals triggered by receptors that recognize microbes and cytokines

Question 67

Kininsystemactivationleadsultimatelytotheformation of bradykinin from its circulating precursor, high- molecular-weight kininogen (HMWK) (Fig. 2–19). Like histamine, bradykinin causes increased vascular perme- ability, arteriolar dilation, and bronchial smooth muscle contraction. It also causes pain when injected into the skin. The actions of bradykinin are short-lived because it is rapidly degraded by kininases present in plasma and tissues. Of note, kallikrein, an intermediate in the kinin cascade with chemotactic activity, also is a potent activator of Hageman factor and thus constitutes another link between the kinin and clotting systems
True or false

Answer 67

True

Question 68

Define chronic inflammation and state three characteristics of it

Answer 68

Chronic inflammation is inflammation of prolonged duration (weeks to years) in which continuing inflammation, tissue injury, and healing, often by fibrosis, proceed simultaneously or is a response of a prolonged duration to an offending agent. In con- trast with acute inflammation, which is distinguished by vascular changes, edema, and a predominantly neutro- philic infiltrate, chronic inflammation is characterized by :
• Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells
• Tissue destruction, largely induced by the products of the inflammatory cells
•Repair,involvingnewvesselproliferation(angiogenesis) and fibrosis

Question 69

What will cause chronic inflammation

How does mycobacterium tuberculosis cause injury

Ureate crystals are not easily engulfed causing strong activation of leukocytes true or false

Leukocytes release chemicals that stimulate growth factor true or false

Chronic inflammation is characterized by?

Cellular infiltrate of chronic inflammation consists of?
What causes the bidirectional interactions between macrophages and T cells

Answer 69

Acute inflammation may progress to chronic inflammation if the acute response cannot be resolved, either because of the persistence of the injurious agent or because of
interference with the normal process of healing.
Alternatively, some forms of injury (e.g., immunologic reactions, some viral infections) engender a chronic inflam- matory response from the outset.

Persistentinfectionsbymicrobesthataredifficulttoerad- icate. These include Mycobacterium tuberculosis, Trepo- nema pallidum (the causative organism of syphilis), and certain viruses and fungi, all of which tend to establish persistent infections and elicit a T lymphocyte–mediated immune response called delayed-type hypersensitivity

• Immune-mediated inflammatory diseases (hypersensitivity diseases). Diseases that are caused by excessive and inap- propriate activation of the immune system are increas- ingly recognized as being important health problems
Under certain conditions, immune reactions develop against the affected person’s own tissues, leading to autoimmune diseases. In such diseases, autoan- tigens evoke a self-perpetuating immune reaction that results in tissue damage and persistent inflammation.
• Prolongedexposuretopotentiallytoxicagents.Examplesare nondegradable exogenous materials such as inhaled particulate silica, which can induce a chronic inflamma- tory response in the lungs (silicosis and endogenous agents such as cholesterol crystals, which may contribute to atherosclerosis ) and endogenous agents (toxic plasma lipid components)

TB prevents the fusion of phagosome w lysosome

Characterized by persistent inflammation, tissue injury,
attempted repair by scarring, and immune response
• Cellular infiltrate consisting of activated macrophages, lymphocytes, and plasma cells, often with prominent
fibrosis
• Mediated by cytokines produced by macrophages and
lymphocytes (notably T lymphocytes), with a tendency to an amplified and prolonged inflammatory response owing to bidirectional interactions between these cells

Question 70

Which cells are usually seen in chronic inflammation
What is the difference between monocytes and macrophages
Where are macrophages found and in each part what is the name of the macrophages found there

Where do monocytes arise from
What happens when monocytes under the influence of adhesion molecules and chemokines
How long do macrophages last(one day)
Which two ways are tissue macrophages activated and explain how those processes work and what they secrete
Alternate pathway is activated by which cytokines and which cells
Name the cytokines released in classical activated pathway (chronic inflammation)
Before tissue repair ,inflammation must be induced and the surface of macrophages have toll like receptors true or false
Name three antigen presenting cells

Answer 70

Macrophages
Lymphocytes(T and B cells)
Plasma cells
Eosinophils

These are Mono nuclear cells

Macrophages, the dominant cells of chronic inflammation, are tissue cells derived from circulating blood monocytes after their emigration from the bloodstream. Macrophages are normally diffusely scattered in most connective tissues and are also found in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (where they are called sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages),limbs

Monocytes arise from precursors in the bone marrow and circulate in the blood for only about a day.

Under the influence of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation, as described earlier. When monocytes reach the extravascular tissue, they undergo transformation into macrophages, which are somewhat larger and have a longer lifespan and a greahter capacity for phagocytosis than do blood monocytes.

Tissue macrophages are activated by Two major
• Classical macrophage activation pathway is induced by two ways namely a.microbial products such as endotoxin, by T cell–derived signals and these activated T Cells secrete the cytokine IFN-γ(interferon gamma) and by foreign
substances including crystals and particulate matter to release certain mediators
b.the interferon gamma released by the T cells induced Classically activated macrophages to produce lysosomal enzymes, NO, and ROS, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate

• Alternative macrophage activation is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells, including mast cells and eosinophils.Alternatively activated macrophages are not actively microbicidal; instead, their principal role is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis and these are all released by the cytokines .

Cytokines in classical- IL-1,IL-12,IL-23 which are responsible for inflammation
Cytokines in alternate-IL-10,TGF beta(transforming growth factor),IL-13,IL-4
These are anti inflammatory agents.

Dendritic cells,B lymphocytes,macrophages

Question 71

State five functions of macrophages

Explain the way macrophages and T cells acute in bidirectional ways

After the initiating stimulus is eliminated and the inflam- matory reaction abates, macrophages eventually die or wander off into lymphatics. In chronic inflammatory sites, however, macrophage accumulation persists, because of continued recruitment from the blood and local prolifera- tion. IFN-γ can also induce macrophages to fuse into large, multinucleate giant cells. True or false

Lymphocytes are mobilized in the setting of any specific immune stimulus (i.e., infections) as well as non–immune- mediated inflammation (e.g., due to ischemic necrosis or trauma), and are the major drivers of inflammation in many autoimmune and other chronic inflammatory dis- eases true or false

How do lymphocytes migrate into inflammatory sites,in the tissues B cells may develop into what ?
What do plasma cells secrete?
What are plasma cells?
Another name for CD4 cells are?
Name the three subsets of T helper cells and what they produce and the functions of what they produce

Both TH1 and TH17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseases. TH2 cells are important in defense against helmin- thic parasites and in allergic inflammation. True or false

Eosinophils are usually found where
And their recruitment is driven by?
Eosinophils bind to what cells to cause production of histamine?

Although the presence of neutro- phils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to show extensive neutro- philic infiltrates, as a result of either persistent microbes or necrotic cells, or mediators elaborated by macrophages. Such inflammatory lesions are sometimes called “acute on chronic”—for example, in inflammation of bones (osteomyelitis). True or false

Mast cells are widely distributed where?

Answer 71

In all tissues, macrophages act as filters for particulate matter, microbes, and senescent cells, as well as the effector cells that eliminate microbes in cel- lular and humoral immune responses,phagocytosis(ingests offending agents and dead tissues) and initiate wound healing

• Macrophages initiate the process of tissue repair and are involved in scar formation and fibrosis.
• Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eico- sanoids.
• Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that
is essential for defense against many microbes by cell- mediated immune responses.

Macrophages present antigens to T cells . The T cells can also produce signals for macrophages to respond to to produce certain mediators. So they can both respond to each other. Macro- phages display antigens to T cells, express membrane mol- ecules (called costimulators), and produce cytokines (IL-12 and others) that stimulate T cell responses Activated T lymphocytes, in turn, produce cytokines, described earlier, which recruit and activate macrophages and thus promote more antigen presentation and cytokine secretion. The result is a cycle of cellular reactions that fuel and sustain chronic inflammation.

.
Both classes of lymphocytes migrate into inflammatory sites using some of the same adhesion molecule pairs and chemokines that recruit other leuko- cytes. In the tissues, B lymphocytes may develop into plasma cells, which secrete antibodies, and CD4+(also known as T helper cells)T lympho- cytes are activated to secrete cytokines.

Plasma cells are terminally differentiated B cells and they produce antibodies

T helper cells (TH)

There are three subsets of CD4+ helper T cells that secrete different sets of cytokines and elicit different types of inflammation:
• TH1 cells produce the cytokine IFN-γ(interferon gamma)
• TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alterna- tive pathway of macrophage activation.
• TH17 cells secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and monocytes into the reaction.

Eosinophils are characteristically found in inflammatory sites around parasitic infections and (more found here) as part of immune reactions mediated by IgE, typically associated with aller- gies. Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific che- mokines (e.g., eotaxin) derived from leukocytes and epithe- lial cells.

Mast cells

Mast cells are sentinel cells widely distributed in connec- tive tissues throughout the body, and they can participate in both acute and chronic inflammatory responses. In atopic persons (those prone to allergic reactions), mast cells are “armed” with IgE antibody specific for certain environmental antigens. When these antigens are subse- quently encountered, the IgE-coated mast cells are trig- gered to release histamines and AA metabolites that elicit the early vascular changes of acute inflammation. True or false
Mast cells have receptors that bind to IgE

Question 72

What is granulomatous inflammation
Granulomas are characteristic of certain pathologic diseases state four ,their cause and tissue reaction
Granulomas can form under three settings name them
Epithelial cells are seen in granulomatous inflammation true or false

Tuberculosis is the proto- type of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified. The formation of a granuloma effectively “walls off” the offending agent and is therefore a useful defense However, granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing or degradation, and granulo- matous inflammation with subsequent fibrosis may even be the major cause of organ dysfunction in some diseases, such as tuberculosis.
true or false

Epithelioid cells are made up of,surrounded by? Frequently what kind of cells are found in granulomas and what do they consist of

Older granulomas may have a rim of fibroblasts and connective tissue. True or false

In granulomas associated with certain infectious organisms (most classically the tubercle bacillus), a combination of hypoxia and free radical injury leads to a central zone of necrosis. On gross examination, this has a granular, cheesy appearance and is therefore called caseous necrosis true or false

Why are granulomas associated with sarcoidosis called non caseating

Name two types of granulomas

Answer 72

Granulomatous inflammation is a distinctive pattern of chronic inflammation characterized by aggregates or accumulation of acti- vated macrophages with scattered T lymphocytes
Occurs when microbes are difficult to eradicate

Tuberculosis -Mycobacterium tuberculosis tissue reaction-Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells;
central necrosis with amorphous granular debris; acid-fast bacilli

Leprosy -Mycobacterium leprae
Acid-fast bacilli in macrophages; noncaseating granulomas

Syphilis -Treponema pallidum
Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic without loss of cellular outline

Cat-scratch disease -Gram-negative bacillus Rounded or stellate granuloma containing central granular debris and neutrophils; giant cells uncommon

Sarcoidosis -Unknown etiology
Noncaseating granulomas with abundant activated macrophages

Crohn disease -Immune reaction against intestinal bacteria ,self antigens
Occasional noncaseating granulomas in the wall of the intestine, with dense bacteria, self antigens chronic inflammatory infiltrate

Granulo- mas can form under three settings:
• With persistent T-cell responses to certain microbes (such as Mycobacterium tuberculosis, T. pallidum, or fungi), in which T cell–derived cytokines are responsible for chronic macrophage activation.
• Granulomas may also develop in some immune- mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease and an important cause of granulomatous inflammation in the United States.
• They are also seen in a disease of unknown etiology called sarcoidosis, and they develop in response to rela- tively inert foreign bodies (e.g., suture or splinter), forming so-called foreign body granulomas.

In the usual H&E preparations some of the activated macrophages in granulomas have pink, granular cytoplasm with indistinct cell boundaries; these are called epithelioid cells because of their resemblance to epithelia. Such cells consist of a large mass of cytoplasm and many nuclei.Typically, the aggregates of epithelioid macrophages are sur- rounded by a collar of lymphocytes.
Frequently, but not invariably, multinucleate giant cells 40 to 50 μm in diameter are found in granulomas. they derive from the fusion of multiple activated macrophages.

The granulomas associated with Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be “non- caseating.” Healing of granulomas is accompanied by fibrosis that may be quite extensive.

Endo
Exo-foreign agents that don’t induce immune response

Question 73

What three things does the systemic effects of inflammation
Or collectively called the acute-phase reaction, or the systemic inflammatory response syndrome comprise of? And explain how they come about
Which cytokines mediate this acute phase reaction ?

IL-6 stimulates the hepatic synthesis of a number of plasma proteins true or false

Which drugs reduce fever

Name three proteins elevated in the acute phase
Synthesis of these molecules is stimulated by which cytokine
How do they eliminate microbes?
What is the basis for measuring ESR as a test for systemic inflammatory response?
Elevated measurements of ESR and CPR are used in assessing what and as a marker of what?

The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some extraor- dinary cases it may reach 40,000 to 100,000 cells/mL. These extreme elevations are referred to as leukemoid reactions because they are similar to those seen in leuke- mia. True or false
Why does leukocytosis occur initially?

What is referred to as shift to the left?

Prolonged infection stimulates production of what factors and when those factors are stimulated what do they cause?

Which type of infections cause increased number of neutrophils and which causes increased number in lymphocytes ,which infections are associated with decreased number of circulating white cells?

Name six other manifestations of the acute phase response

In severe bacterial infections (sepsis), the large amounts of bacterial products in the blood or extravascular tissue stimulate the production of several cytokines, notably TNF, as well as IL-12 and IL-1. TNF can cause dissemi- nated intravascular coagulation (DIC), metabolic distur- bances including acidosis, and hypotensive shock. This clinical triad is described as septic shock;true or false

Even before the inflammatory reaction ends, the body begins the process of healing the damage and restoring normal structure and this is called repair true or false

Answer 73

The cyto- kines TNF, IL-1, and IL-6 are the most important mediators of the acute-phase reaction. These cytokines are produced by leukocytes (and other cell types) in response to infection or in immune reactions and are released systemically.

1.Fever, characterized by an elevation of body tempera- ture, is one of the most prominent manifestations of the acute-phase response. Bacterial products, such as lipopolysaccharide (LPS) (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens)
Fever is caused in response to pyrogens. These pyrogens cause synthesis of prostaglandins in the hypothalamus by increasing the level of Cox which converts AA into prostaglandin.The prostaglandin synthesized especially PGE2 causes the hypothalamus to secrete neurotransmitters that reset the temperature set point at a higher level

NSAIDs, including aspirin, reduce fever by inhibiting cyclooxygenase and thus blocking prosta- glandin synthesis.

2.• Elevatedplasmalevelsofacute-phaseproteins.These plasma proteins are mostly synthesized in the liver, and in the setting of acute inflammation, their concentrations may increase several hundred-fold. Three of the best known of these proteins are C-reactive protein (CRP), fibrino- gen, and serum amyloid A (SAA) protein. Synthesis of these molecules by hepatocytes is stimulated by cyto- kines, especially IL-6. Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement, thus promot- ing the elimination of the microbes.

Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than indi- vidual erythrocytes. This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response, caused by any number of stimuli, including LPS.

Serial measurements of ESR and CRP are used to assess therapeutic responses in patients with inflammatory disorders such as rheu- matoid arthritis. Elevated serum levels of CRP are now used as a marker for increased risk of myocardial infarc- tion or stroke in patients with atherosclerotic vascular disease. It is believed that inflammation is involved in the development of atherosclerosis and increased CRP is a measure of inflammation.

3.Leukocytosis is a common feature of inflammatory reac- tions, especially those induced by bacterial infection .

The leukocytosis occurs initially because of acceler- ated release of cells (under the influence of cytokines, including TNF and IL-1) from the bone marrow postmi- totic reserve pool. Both mature and immature neutro- phils may be seen in the blood;

the presence of circulating immature cells is referred to as a “shift to the left.” Pro- longed infection also stimulates production of colony- stimulating factors (CSFs), which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells in the inflammatory reaction.

Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, are associated with increased numbers of lymphocytes (lymphocytosis). Bronchial asthma, hay fever, and parasite infestations all involve an increase in the absolute number of eosinophils, creating an
eosinophilia.
Certain infections (typhoid fever and infec- tions caused by some viruses, rickettsiae, and certain protozoa) are paradoxically associated with a decreased number of circulating white cells (leukopenia), likely because of cytokine-induced sequestration of lympho- cytes in lymph nodes.

• Other manifestations of the acute-phase response include increased heart rate and blood pressure; decreased sweating, mainly as a result of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; and rigors (shiver- ing), chills (perception of being cold as the hypothala- mus resets the body temperature), anorexia, somnolence, and malaise, probably secondary to the actions of cyto- kines on brain cells.

Summary
Systemic Effects of Inflammation
• Fever: cytokines (TNF, IL-1) stimulate production of pros- taglandins in hypothalamus
• Production of acute-phase proteins: C-reactive protein, others; synthesis stimulated by cytokines (IL-6, others) acting on liver cells
• Leukocytosis: cytokines (CSFs) stimulate production of leukocytes from precursors in the bone marrow
• In some severe infections, septic shock: fall in blood pres- sure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF

Question 74

What is repair and which two ways does it occur
What is regeneration and how does it occur?

Regeneration It is the typical response to injury in the rapidly dividing epithelia of the skin and intestines, and some parenchymal organs, notably the liver. True or false

What causes scar formation
What is fibrosis
What is organization in inflammation?

Although the fibrous scar cannot perform the function of lost parenchymal cells, it pro- vides enough structural stability that the injured tissue is usually able to function. True or false?

Answer 74

Repair, sometimes called
healing, refers to the restoration of tissue architecture and function after an injury. It occurs by two types of reactions: regeneration of the injured tissue and scar formation by the deposition of connective tissue
• Regeneration. Some tissues are able to replace the damaged cells and essentially return to a normal state; this process is called regeneration. Regeneration occurs by proliferation of residual (uninjured) cells that retain the capacity to divide, and by replacement from tissue stem cells.
• Scar formation. If the injured tissues are incapable of regeneration, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that results in scar formation.

. The term fibrosis is most often used to describe the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarc- tion).

If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called organization (as in organizing pneumonia affecting the lung).

Question 75

The regeneration of injured cells and tissues involves cell proliferation what drives this?
Name three cells that proliferate during tissue repair and what drives this proliferation
What factors determine the adequacy of the repair process
What three things determine the normal size of a cell population
What are the two key processes in cell proliferation and what is the cell cycle

Where are non dividing cells found in the cell cycle

What do growth factors do in cell cycle?
What regulates procession and what controls cyclins and once cells enter S phase what happens?

What influences the ability of tissues I repair themselves?
On the basis of this the tissues of the body are divided into three name them
Name three cells in the body that are labile cells and one characteristic of them each

Labile tissues can readily regenerate after injury as long as the pool of stem cells is preserved.true or false

Which cells are capable of proliferating in response to injury or lost mass of tissue
Give three examples of stable cells

With the exception of liver, stable tissues have a limited capacity to regenerate after injury. True or false

What kind of cells belong to the permanent tissue type

Limited stem cell replication and differentiation occur in some areas of the adult brain, and there is some evidence that
cells may proliferate after myocardial necrosis. Never- theless, whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue regenera- tion after injury. Skeletal muscle is usually classified as a permanent tissue, but satellite cells attached to the endomysial sheath provide some regenerative capacity for this tissue. True or false

With the exception of tissues composed primarily of non- dividing permanent cells (e.g., cardiac muscle, nerve), most mature tissues contain variable proportions of three cell types. Name them

Answer 75

which is driven by growth factors and is criti- cally dependent on the integrity of the extracellular matrix.

These include the remnants of the injured tissue (which attempt to restore normal structure), vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process), and fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be cor- rected by regeneration). The proliferation of these cell types is driven by proteins called growth factors.

The production of polypeptide growth factors and the ability of cells to divide in response to these factors

by a balance among cell proliferation, cell death by apoptosis, and emergence of new differentiated cells from stem cells .

The key processes in the proliferation of cells are DNA replication and mitosis. The sequence of events that control these two processes is known as the cell cycle,

nondividing cells are in cell cycle arrest in the G1 phase or have exited the cycle and are in the G0 phase.

Growth factors stimulate cells to transition from G0 into the G1 phase and beyond into DNA synthesis (S), G2, and mitosis (M) phases.

Progression is regulated by cyclins, whose activity is controlled by cyclin- dependent kinases. Once cells enter the S phase, their DNA is replicated and they progress through G2 and mitosis.

Proliferative Capacities of Tissues
The ability of tissues to repair themselves is critically influ- enced by their intrinsic proliferative capacity. On the basis of this criterion, the tissues of the body are divided into three groups.
• Labile (continuously dividing) tissues. Cells of these tissues are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells.

Labile cells include hematopoietic cells in the bone marrow and the majority of surface epithelia, such as the stratified squamous surfaces of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pan- creas, biliary tract); the columnar epithelium of the gas- trointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract.
•
Stable tissues. Cells of these tissues are quiescent and have only minimal replicative activity in their normal state. However, these cells are capable of proliferating in response to injury or loss of tissue mass. Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas. They also include endothe- lial cells, fibroblasts, and smooth muscle cells; the pro- liferation of these cells is particularly important in wound healing.

• Permanent tissues. The cells of these tissues are consid- ered to be terminally differentiated and nonproliferative in postnatal life. In permanent tissues, repair is typically dominated by scar formation.

Most neurons and cardiac muscle cells belong to this category. Thus, injury to brain or heart is irreversible and results in a scar, because neurons and cardiac myocytes cannot regenerate.

: continuously dividing cells, quiescent cells that can return to the cell cycle, and cells that have lost replicative ability.

Question 76

As mature cells die, the tissue is replenished by the differentiation of cells gener- ated from?

In which tissues is a there a homeostatic equilibrium between the replication, self- renewal, and differentiation of stem cells and the death of the mature, fully differentiated cells. Such relationships are particularly evident in the continuously dividing epithe- lium of the skin and the gastrointestinal tract, in which stem cells live near the basal layer of the epithelium, and cells differentiate as they migrate to the upper layers of the epithelium before they die and are shed from the surface?

Name two characteristics of stem cells
Explain them
State the two types of stem cells

Although, like ES cells, adult stem cells they also have self-renewal capacity, this property is much more limited. In addition, their lineage potential (ability to give rise to specialized cells) is restricted to some or all of the differentiated cells of the tissue or organ in which they are found.
Whereas the normal function of ES cells is to give rise to all cells of the body, adult stem cells are involved in tissue homeostasis. They maintain the compartment size both in tissues with high turnover, such as skin, bone marrow, and gut epithelium, and in those with low cell turnover,
such as heart and blood vessels. True or false

tissue stem cells are rare and very difficult to isolate to purity. Apparently signals from other cells in such niches keep the stem cells quiescent and undifferentiated. True or false

What kind of stem cells can be isolated

Answer 76

stem cells.

Stem cells

Stem cells are characterized by two important properties: self- renewal capacity and asymmetric replication.

Asymmetric rep- lication means that when a stem cell divides, one daughter cell enters a differentiation pathway and gives rise to mature cells, while the other remains an undifferentiated stem cell that retains its self-renewal capacity. Self-renewal enables stem cells to maintain a functional population of precursors for long periods of time.

• Embryonic stem cells (ES cells) are the most undifferenti- ated stem cells. They are present in the inner cell mass of the blastocyst and have extensive cell renewal capac- ity. Hence they can be maintained in culture for over a year without differentiating. Under appropriate culture conditions, ES cells can be induced to form specialized cells of all three germ cell layers, including neurons, cardiac muscle, liver cells, and pancreatic islet cells.
• Adult stem cells, also called tissue stem cells, are less undifferentiated than ES cells and are found among dif- ferentiated cells within an organ or tissue.

Hematopoietic stem cells can be isolated from bone marrow as well as from the peripheral blood after mobilization by administration of certain cytokines such as granulocyte colony-stimulating factor

Question 77

• Regeneration of tissues is driven by proliferation of unin- jured (residual) cells and replacement from stem cells.
• Cell proliferation occurs when quiescent cells enter the cell cycle.The cell cycle is tightly regulated by stimulators and inhibitors and contains intrinsic checkpoint controls to prevent replication of abnormal cells.
• Tissues are divided into labile, stable, and permanent, according to the proliferative capacity of their cells.
• Continuously dividing tissues (labile tissues) contain mature cells that are capable of dividing and stem cells that differentiate to replenish lost cells.
• Stem cells from embryos (ES cells) are pluripotent; adult tissues, particularly the bone marrow, contain adult stem cells capable of generating multiple cell lineages.
• Induced pluripotent stem cells (iPS cells) are derived by introducing into mature cells genes that are characteristic of ES cells. iPS cells acquire many characteristics of stem cells.
True or false

Answer 77

True

Question 78

Name four functions of growth factors and state what produces them

Answer 78

They induce cell proliferation by binding to specific receptors and affecting the expression of genes whose products typically have several functions: They promote entry of cells into the cell cycle, they relieve blocks on cell cycle progression (thus promoting replication), they prevent apoptosis, and they enhance the synthesis of cellular proteins in preparation for mitosis. A major activity of growth factors is to stimulate the function of growth control genes, many of which are called proto-oncogenes because mutations in them lead to unrestrained cell proliferation characteristic of cancer (oncogenesis)

Many of the growth factors that are involved in repair are produced by macrophages and lymphocytes that are recruited to the site of injury or are activated at this site, as part of the inflammatory process. Other growth factors are produced by parenchymal cells or stromal (connective tissue) cells in response to cell injury.

Question 79

Most growth factors function by binding to specific cell- surface receptors and triggering biochemical signals in cells. The major intracellular signaling pathways induced by growth factor receptors are similar to those of many other cellular receptors that recognize extracellular ligands. In general, these signals lead to the stimulation or repres- sion of gene expression. Signaling may occur directly in the same cell that produces the factor (autocrine signaling), between adjacent cells (paracrine signaling), or over greater distances (endocrine signaling).
True or false

Receptor proteins are generally located on the cell surface, but they may be intracellular; in the latter case, the ligands must be sufficiently hydrophobic to enter the cell (e.g., vitamin D, or steroid and thyroid hormones). True or false

Name three types of plasma membrane receptors ,their signaling mechanisms and the ligands

State the importance of StATs in receptors without intrinsic enzyme activity
What signaling pathway causes the release of calcium

Answer 79

True
True

1.Receptors with intrinsic kinase activity. Ligand binding to one chain of the receptor activates tyrosine kinase on the other chain, resulting in activation of multiple downstream signaling pathways
(RAS-MAP kinase, PI-3 kinase, PLC-γ) that lead to cell proliferation and activation of various transcription factors. Ligands:Epidermal growth factors,fibroblast growth factors,vascular endothelial growth factors,hepatocyte growth factor
PI3( phosphatidylinositol-3; )PLC-γ, (phospholipase Cγ)MAP, (microtubule-associated protein;)

2.• G protein–coupled seven transmembrane receptors: Ligand binding induces switch from GDP-bound inactive form of associated G protein to GTP-bound active form; activates cAMP(cAMP, cyclic adenosine monophosphate )Ca2+ influx leading to increased cell motility; multiple other effects. Ligands: Multiple inflammatory mediators, hormones, all chemokines

3.Receptors without intrinsic enzymatic activity. : Ligand binding recruits kinases (e.g., Janus kinases [JAKs]) that phosphorylate and activate transcription factors (e.g., signal transducers and activators of transcription [STATs]). Ligands: Many cytokines including enzymatic activity interferons, growth
hormone, CSFs(colony-stimulating factors) EPO(epopoietin)

Phosphorylation of JAKs activates cytoplasmic transcription factors called STATs (signal transducers and activators of transcription), which shuttle into the nucleus and induce transcription of target genes.

Among the several signaling pathways activated through G protein– coupled receptors are those involving cyclic AMP (cAMP), and the generation of inositol 1,4,5-triphosphate (IP3), which releases calcium from the endoplasmic reticulum. Receptors in this category constitute the largest family of plasma membrane receptors

Question 80

Name three roles of the EcM and state how those roles are carried out
The forms it occurs in ,where those forms are found,what synthesizes them, and what are found in them
What forms the specialized basement membrane
And what are the three basic components of ECM
There are 30collagen types
What type of collagen forms a major proportion of connective tissue in healing
•

The tensile strength of the fibrillar collagens derives from their cross-linking, which is the result of covalent bonds catalyzed by the enzyme lysyl-oxidase, what does this process depend on and what problems do individuals with Vit C deficiency face

Genetic defects in fibrillar collagens cause which diseases?

Non fibrillar collagens form what?
although labile and stable cells are capable of regeneration, An intact ECM is required for tissue regeneration, and if the ECM is damaged, repair can be accomplished only by scar formation.true or false

Tissue repair depends not only on growth factor activity but also on interactions between cells and ECM compo- nents. The type of ECM proteins can affect the degree of differentiation of the cells in the tissue, again acting largely through cell surface integrins True or false

Answer 80

ECM sequesters water, providing turgor to soft tissues, and minerals, giving rigidity to bone. by supplying a substrate for cell adhesion and migration and serving as a reservoir for growth factors.
• ECM regulates cell proliferation by binding and displaying growth factors and by signaling through cellular recep- tors of the integrin family..
• Scaffolding for tissue renewal. Because maintenance of normal tissue structure requires a basement membrane or stromal scaffold, the integrity of the basement mem- brane or the stroma of parenchymal cells is critical for the organized regeneration of tissues.
• Establishment of tissue microenvironments. Basement mem- brane acts as a boundary between epithelium and underlying connective tissue and also forms part of the filtration apparatus in the kidney.
S

• Interstitial matrix: This form of ECM is present in the spaces between cells in connective tissue, and between epithelium and supportive vascular and smooth muscle structures. It is synthesized by mesenchymal cells (e.g., fibroblasts) and tends to form a three-dimensional, amorphous gel. Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, pro- teoglycans, hyaluronate,

• Basement membrane:. The basement membrane lies beneath the epithelium and is synthesized by overlying epithelium and underlying mesenchymal cells; it tends to form a platelike “chicken wire” mesh. Its major constituents are
amorphous nonfibrillar type IV collagen and laminin

The seemingly random array of interstitial matrix in connective tissues becomes highly organized around epithelial cells, endothelial cells, and smooth muscle cells, forming the specialized basement membrane

There are three basic components of ECM: (1) fibrous struc- tural proteins such as collagens and elastins, which confer tensile strength and recoil; (2) water-hydrated gels such as proteoglycans and hyaluronan, which permit resilience and lubrication; and (3) adhesive glycoproteins that connect the matrix elements to one another and to cells

Collagen
Some collagen types (e.g., types I, II, III, and V) form fibrils by virtue of lateral cross-linking of the triple helices. The fibrillar collagens form a major proportion of the connective tissue in healing wounds and particularly in scars.

This process is dependent on vitamin C; therefore, individuals with vitamin C deficiency have skeletal deformities, bleed easily because of weak vascular wall basement membrane, and suffer from poor wound healing.

Genetic defects in these collagens cause diseases such as osteogenesis imperfecta and Ehlers-Danlos syn- drome.

Other collagens are nonfibrillar and may form base- ment membrane (type IV) or be components of other structures such as intervertebral disks (type IX) or dermal– epidermal junctions (type VII).

Question 81

The ability of tissues to recoil and return to a baseline structure after physical stress is conferred by elastic tissue,where is this ability especially important

Morphologically, elastic fibers consist of a central core of elastin surrounded by?

Defects in fibrillin synthesis leads to?

What do proteoglycans confer?
Name two functions of Hyaluronan
Name two functions of proteoglycans
What serve as reservoirs for growth factors secreted into the ECM (e.g., fibroblast growth factor [FGF], HGF).

Adhesion receptors are grouped into four name them and are made up of what?

Fibronectinis synthesized by? And binds to integrins by?

Tissue fibronec- tin forms fibrillar aggregates at wound healing sites; plasma fibronectin binds to fibrin within the blood clot that forms in a wound, providing the substratum for ECM deposition and re-epithelialization true or false

Laminin is the most abundant glycoprotein in basement membrane. True or false
Name three functions of laminin

Integrins mediate leukocyte adhesion to endothelium. They are also the main cellular receptors for ECM components, such as fibronectins and laminins.
True or false

integrins as leukocyte surface molecules that mediate firm adhesion and transmigration across endothelium at sites of inflammation, Integrins are present in the plasma mem- brane of most cells, with the exception of red blood cells. They bind to many ECM components through RGD motifs, initiating signaling cascades that can affect cell locomotion, proliferation, and differentiation true or false

Answer 81

This is especially important in the walls of large vessels (which must accommodate recurrent pulsatile flow), as well as in the uterus, skin, and ligaments.

a meshlike network of fibrillin glycoprotein.

Defects in fibrillin synthesis lead to skeletal abnormalities and weak- ened aortic walls (as in Marfan syndrome

Proteoglycans form highly hydrated compressible gels conferring resilience and lubrication (such as in the carti- lage in joints).

Hyaluronan (also called hyaluronic acid), a huge mucopolysaccharide without a protein core, is also an important constituent of the ECM that binds water, and forms a viscous, gelatin-like matrix.

proteoglycans

Some pro- teoglycans are integral cell membrane proteins that have roles in cell proliferation, migration, and adhesion—for example, by binding growth factors and chemokines and providing high local concentrations of these mediators.

The adhesion receptors, also known as cell adhesion molecules (CAMs), are grouped into four families—immunoglobulins, cadherins, selectins, and integrins

Laminin and fibronectin

• Fibronectin is synthesized by a variety of cells, including fibro- blasts, monocytes, and endothelium that exists in tissue and plasma forms.
Fibronectins can also attach to cell integrins via a tripeptide arginine–glycine– aspartic acid (abbreviated RGD) motif.

.
• It connects cells to underlying ECM components such as type IV collagen and heparan sulfate.
Besides mediat- ing attachment to basement membrane, laminin can also modulate cell proliferation, differentiation, and motility.
•

Question 82

Role of regeneration in tissue repair

The importance of regeneration in the replacement of injured tissues varies in different types of tissues and with the severity of injury. True or false

In labile tissues, such as the epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells provided ?

How is loss of blood cells corrected in labile tissues

Tissue regeneration occurs in which kind of organs? What organs have some kind of regenerative capacity?

The surgical removal of a kidney elicits in the contralateral kidney a compensatory response that con- sists of both hypertrophy and hyperplasia of proximal duct cells. True or false

• The regenerative response of the liver that occurs after surgical removal of hepatic tissue is remarkable and unique among all organs true or false

In experimental systems, hepatocyte replication after partial hepatectomy is initiated by ?

Pro- gression through the cell cycle is dependent on the activity of ?

extensive regeneration or compensatory hyperplasia will occur if what is intact and give an example

Answer 82

• the underlying basement membrane is intact.

Loss of blood cells is corrected by proliferation of hematopoietic progenitors in the bone marrow and other tissues, driven by CSFs, which are produced in response to the reduced numbers of blood cells.

• Tissue regeneration can occur in parenchymal organs with stable cell populations, but with the exception of the liver, this is usually a limited process. Pancreas, adrenal, thyroid, and lung have some regenerative capacity.

cytokines (e.g., TNF, IL-6) that prepare the cells for replication by stimu- lating the transition from G0 to G1 in the cell cycle.

growth factors such as HGF (produced by fibroblasts, endothelial cells, and liver nonparenchymal cells) and the EGF family of factors, which includes transforming growth factor-α (TGF-α) (produced by many cell types).

only if the residual connec- tive tissue framework is structurally intact, as after partial surgi- cal resection. By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring. For example, extensive destruction of the liver with collapse of the reticulin framework, as occurs in a liver abscess, leads to scar formation even though the remaining liver cells have the capacity to regenerate.

Question 83

Under what conditions will repair occur by replace- ment of the nonregenerated cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some cells and scar formation?

What are the steps in scar formation?

When does repair occur and explain how scars form

The term granulation tissue derives from the gross appear- ance, such as that beneath the scab of a skin wound. Its histologic appearance is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angio- genesis) in a loose ECM, often with admixed inflammatory cells, mainly macrophages. True or false

What is angiogenesis

Angiogenesis is critical in healing at sites of injury, in the development of collateral circulations at sites of ischemia, and in allowing tumors to increase in size beyond the constraints of their original blood supply. True or false

What are the 7 steps of angiogenesis

Name the most important growth factors that contribute to angiogenesis

What does the family of VEGF comprise of and state what they’re involved in

Where are VEGFs mostly expressed

What induces VEGFS and what is the function of VEGFS

Released FGF can bind to heparan sulfate and be stored in the ECM true or false
How does FGF-2 participate in Angiogenesis

What are the functions of angiopoietin

How are newly formed vessels stabilized ?
Name two other growth factors that help in the stabilization

What suppresses endothelial proliferation and migration, and enhances the produc- tion of ECM proteins?

What is vasculogenesis?

Where are angioblasts derived from?

How do ECM proteins help in angiogenesis

Why are newly formed vessels leaky

Answer 83

if tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as the connective tissue, or if nondividing cells are injured, repair cannot be accomplished by regeneration alone.

Repair by connective tissue deposition consists of sequen- tial processes that follow the inflammatory response :
• Formation of new blood vessels (angiogenesis)
• Migration and proliferation of fibroblasts and deposi- tion of connective tissue, which, together with abundant vessels and interspersed leukocytes, has a pink, granular
appearance and hence is called granulation tissue
• Maturation and reorganization of the fibrous tissue
(remodeling) to produce the stable fibrous scar

Repair begins within 24 hours of injury by the emigration of fibroblasts and the induction of fibroblast and endothe- lial cell proliferation. By 3 to 5 days, the specialized granu- lation tissue that is characteristic of healing is apparent. Granulation tissue progressively accumulates more fibroblasts, which lay down collagen, eventually resulting in the formation of a scar .Scars remodel over time.

Angiogenesis is the process of new blood vessel development from existing vessels, primarily venules.
Angiogenesis involves sprouting of new vessels from existing ones and consists of the following steps :
•Vasodilation occurring in response to NO and increased permeability induced by VEGF
• Separation of pericytes from the abluminal surface
• Migration of endothelial cells toward the area of tissue
injury
.Proliferation of endothelial cells just behind the leading front of migrating cells
• Remodeling into capillary tubes
• Recruitment of periendothelial cells (pericytes for small
capillaries and smooth muscle cells for larger vessels) to
form the mature vessel
• Suppression of endothelial proliferation and migration
and deposition of the basement membrane

VEGF and basic fibroblast growth factor (FGF-2), Angiopoietins Ang1andAng2

The VEGF family of growth factors includes VEGF-A, -B, -C, -D, and -E and placental growth factor (PlGF). VEGF-A is generally referred to as VEGF and is the major inducer of angiogenesis after injury and in tumors; VEGF-B and PlGF are involved in vessel development in the embryo; and VEGF-C and -D stimulate both lym- phangiogenesis and angiogenesis.

epithelial cells adjacent to fenestrated epithelium (e.g., podocytes in the kidney, pigment epithelium in the retina).

They bind to a family of tyrosine kinase recep- tors (VEGFR-1, -2, and -3).
Most important receptor is VEGFR-2 and it’s expressed by endothelial cells

hypoxia is the most important; others are platelet-derived growth factor (PDGF), TGF-α, and TGF-β.

Functions:VEGF stimulates both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis. It promotes vasodilation by stimulating the production of NO, and contributes to the formation of the vascular lumen

FGF-2 participates in angiogenesis mostly by stimulating the proliferation of endothelial cells. It also promotes the migration of macrophages and fibro- blasts to the damaged area, and stimulates epithelial cell migration to cover epidermal wounds.

• Angiopoietins Ang1andAng2 aregrowthfactorsthatplay a role in angiogenesis and the structural maturation of new vessels.

Newly formed vessels need to be stabilized by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue.

Ang1 inter- acts with a tyrosine kinase receptor on endothelial cells called Tie2.

The growth factors PDGF and TGF-β also participate in the stabilization process—

TGF-β does that and PDGF recruits smooth muscle cells and

The growth of blood vessels during embryonic develop- ment is called vasculogenesis. In vasculogenesis, vessels are formed de novo by the coalescence of endothelial precur- sors called angioblasts. Angioblasts are derived from hemangioblasts, which also provide the precursors of the hematopoietic system.

ECM proteins participate in the process of vessel sprout- ing in angiogenesis, largely through interactions with in- tegrin receptors in endothelial cells and by providing the scaffold for vessel growth.

Newly formed vessels are leaky because of incomplete interendothelial junctions and because VEGF increases vascular permeability. This leakiness explains why granu- lation tissue is often edematous and accounts in part for the edema that may persist in healing wounds long after the acute inflammatory response has resolved. Further- more, it leads to high intratumoral pressure and is the basis for the edema that is so problematic in ocular angio- genesis in pathologic processes such as wet macular degeneration.

Question 84

Which two ways does laying down of connective tissue occur?
What growth factors drive this process
What are the major sources of these factors

Sites of inflamma- tion are also rich in mast cells, and in the appropriate chemotactic milieu, lymphocytes may be present as well. Each of these cell types can secrete cytokines and growth factors that contribute to fibroblast proliferation and activation. True or false

What causes increased deposition of ECM

What are the the growth factors involved in deposition of ECM and scar formation

Name two functions of Transforming growth factor-β (TGF-β)

TGF-β is involved not only in scar formation after injury but
also in the development of fibrosis in lung, liver, and
kidneys that follows chronic inflammation. True or false

Where is PDGF stored,how is it released ,what produces it, and what is its importance in inflammation

How do cytokines participate in scar formation of ECM deposition

Answer 84

1) migration and proliferation of fibroblasts into the site of injury and (2) deposition of ECM proteins produced by these cells.

The recruitment and activation of fibroblasts to syn- thesize connective tissue proteins are driven by many growth factors, including PDGF, FGF-2 (described earlier), and TGF-β.

The major source of these factors is inflamma- tory cells, particularly macrophages, which are present at sites of injury and in granulation tissue.

As healing progresses, the number of proliferating fibroblasts and new vessels decreases; however, the fibro- blasts progressively assume a more synthetic phenotype, so there is increased deposition of ECM.

TGF-β, PDGF, and FGF,cytokines

1.TGF-β stimulates the production of collagen, fibro- nectin, and proteoglycans, and it inhibits collagen degradation by both decreasing proteinase activity and increasing the activity of tissue inhibitors of pro- teinases known as TIMPs
2.TGF-β is an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses. It does so by inhibiting lymphocyte proliferation and the activity of other leukocytes. Mice lacking TGF-β exhibit widespread inflammation and abundant lym-
phocyte proliferation.
•

Platelet-derived growth factor (PDGF)
is stored in platelets and released on platelet activation and is also produced by endothelial cells, activated macrophages, smooth muscle cells, and many tumor cells. PDGF causes migration and proliferation of fibroblasts and smooth muscle cells and may contribute to the migra- tion of macrophages.

Cytokines may also function as growth factors and par- ticipate in ECM deposition and scar formation. IL-1 and IL-13, for example, act on fibroblasts to stimulate colla- gen synthesis, and can also enhance the proliferation and migration of fibroblasts.

Question 85

After its synthesis and deposition, the connective tissue in the scar continues to be modified and remodeled. Thus, the outcome of the repair process is a balance between synthe- sis and degradation of ECM proteins. What degrades ECM proteins

MMPs should be distinguished from neutrophil elastase, cathep- sin G, plasmin, and other serine proteinases that can also degrade ECM but are not metalloenzymes.true or false

What do MMPs include and the things they degrade
What produces MMPs and what regulates MMPs
How is MMPs tightly regulated

Repair by connective tissue deposition involves angiogen- esis, migration and proliferation of fibroblasts, collagen synthesis, and connective tissue remodeling.
• Repair by connective tissue starts with the formation of granulation tissue and culminates in the laying down of fibrous tissue.
• Multiple growth factors stimulate the proliferation of the cell types involved in repair.
• TGF-β is a potent fibrogenic agent; ECM deposition depends on the balance among fibrogenic agents, the metalloproteinases (MMPs) that digest ECM, and the TIMPs.
True or false

Answer 85

matrix metalloproteinases (MMPs), which are dependent on zinc ions for their activity.

MMPs include interstitial collagenases, which cleave fibrillar collagen (MMP-1, -2, and -3); gelatinases (MMP-2 and -9), which degrade amorphous collagen and fibronectin; and strome- lysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibro- nectin, and amorphous collagen.

MMPs are produced by a variety of cell types (fibro- blasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regu- lated by growth factors, cytokines, and other agents.

The activity of the MMPs is tightly controlled. They are produced as inactive precursors (zymogens) that must be first activated; this is accomplished by proteases (e.g., plasmin) likely to be present only at sites of injury.
In addition, acti- vated MMPs can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells. Therefore during scarring, MMPs are activated to remodel the deposited ECM, and then their activity is shut down by the TIMPs.

Question 86

Name six factors influence tissue repair or wound healing
What are keloids?

State two clinically significant types of repair

Cutaneous wound healing is a process that involves both epithelial regeneration and the formation of connective tissue scar and is thus illustrative of the general principles that apply to healing in all tissues.true or false

What are the type of cutaneous healing of skin wounds and what do they depend on

What is healing by first intention or primary union and healing by second intention

What are the four differences between first and second intention

Answer 86

.Infection is clinically the most important cause of delay in healing; it prolongs inflammation and potentially increases the local tissue injury.Diabetes.
• Nutrition has profound effects on repair; protein defi- ciency, for example, and especially vitamin C deficiency inhibit collagen synthesis and retard healing.
• Glucocorticoids (steroids) have well-documented anti- inflammatory effects, and their administration may result in weakness of the scar because of inhibition of
TGF-β production and diminished fibrosis. In some instances, however, the anti-inflammatory effects of glu- cocorticoids are desirable. For example, in corneal infec- tions, glucocorticoids are sometimes prescribed (along with antibiotics) to reduce the likelihood of opacity that may result from collagen deposition.
-Mechanical variables such as increased local pressure or torsion may cause wounds to pull apart, or dehisce. -Poorperfusion,dueeithertoarteriosclerosisanddiabetes or to obstructed venous drainage (e.g., in varicose veins), also impairs healing.
-Foreign bodies such as fragments of steel, glass, or even bone impede healing.
-The type and extent of tissue injury affects the subse- quent repair. type, volume, and loca- tion of the injury .Complete restoration can occur only in tissues composed of stable and labile cells; injury to tissues composed of permanent cells must inevitably result in scarring, as in healing of a myocardial infarct.
-The location of the injury and the character of the tissue in which the injury occurs are also important. For example, inflammation arising in tissue spaces (e.g., pleural, peritoneal, or synovial cavities) develops exten- sive exudates.

-AberrationsofcellgrowthandECMproductionmayoccur even in what begins as normal wound healing. For example, the accumulation of exuberant amounts of col- lagen can give rise to prominent, raised scars known as keloids . Excessive production of ECM causes keloids

the healing of skin wounds (cutaneous wound healing) and fibrosis in injured parenchymal organs

Depending on the nature and size of the wound, the healing of skin wounds is said to occur by first or second intention.

One of the simplest examples of wound repair is the healing of a clean, uninfected surgical incision approximated by surgical sutures The incision causes only focal disruption of epithelial basement membrane continuity and death of relatively few epithelial and con- nective tissue cells. As a result, epithelial regeneration is the principal mechanism of repair. A small scar is formed, but there is minimal wound contraction. The narrow incisional space first fills with fibrin-clotted blood, which then is rapidly invaded by granulation tissue and covered by new epithelium.

Second intention:

When cell or tissue loss is more extensive, such as in large wounds, at sites of abscess formation, ulceration, and isch- emic necrosis (infarction) in parenchymal organs, the repair process is more complex and involves a combination of regeneration and scarring. In second intention healing of skin wounds, also known as healing by secondary union ,the inflammatory reaction is more intense, and there is development of abundant granu- lation tissue, with accumulation of ECM and formation of a large scar, followed by wound contraction mediated by the action of myofibroblasts

-A larger clot or scab rich in fibrin and fibronectin forms at the surface of the wound.
• Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. Consequently, large defects have a greater potential for secondary, inflammation-mediated, injury.
• Larger defects require a greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium. A greater volume of granulation tissue generally results in a greater mass of scar tissue.
• Secondary healing involves wound contraction and more extensive scarring.Within 6 weeks, for example, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction. This process has been ascribed to the presence of myo- fibroblasts, which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.

Question 87

Wound Strength
Carefully sutured wounds have approximately 70% of the strength of normal skin, largely because of the placement of sutures. When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks. The recovery of tensile strength results from collagen synthesis exceeding degradation during the first 2 months, and from structural modifications of collagen (e.g., cross-linking, increased fiber size) when synthesis declines at later times. Wound strength reaches approximately 70% to 80% of normal by 3 months and usually does not improve substan- tially beyond that point.
True or false

What is fibrosis

State the difference between fibrosis and tissue repair

Answer 87

True

Fibrosis in Parenchymal Organs
Deposition of collagen is part of normal wound healing. The term fibrosis is used to denote the excessive deposition of collagen and other ECM components in a tissue. As already mentioned, the terms scar and fibrosis are used interchangeably, but fibrosis most often refers to the deposi- tion of collagen in chronic diseases.. Persistent stimulation of collagen synthesis in chronic inflammatory diseases leads to fibrosis of the tissue.

The basic mechanisms of fibrosis are the same as those of scar formation during tissue repair. However, tissue repair typically occurs after a short-lived injurious stimu- lus and follows an orderly sequence of steps, whereas fibrosis is induced by persistent injurious stimuli such as infections, immunologic reactions, and other types of tissue injury.