Inflammation 1

Question 1

What is fibrosis?

Answer 1

the thickening and scarring of connective tissue, usually as a result of injury. (result of chronic inflammation)

Question 2

How does inflammation act as a protective function?

Answer 2

Dilutes, destroys or neutralizes harmful agents (bacteria, necrotic tissue)

Sets into motion the process of repair

Main components:
Vascular reaction and Cellular response (intertwined)

Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can themselves cause consider- able harm

Question 3

What are the 5 R’s of inflammation

Answer 3

(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 external manifestations of inflammation, often called its cardinal signs, are heat (calor), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa)

Question 4

What are some of features of acute inflammation?

Answer 4

Fast onset: minutes or hours
Mainly neutrophils
Tissue injury usually mild
Local and systemic signs are often prominent

Question 5

What are some of features of chronic inflammation?

Answer 5

Monocytes/macrophages and lymphocytes
Tissue injury/fibrosis is often severe and progressive
Local and systemic signs are often less prominent and may be subtle

Question 6

What are the basic phases of acute inflammation?

Answer 6

Transient Vasoconstriction: (lasting only for seconds)

Vasodilation (primary): leads to greater blood flow to the area of inflammation (floods downstream capillary beds), resulting in redness and heat (erythema and warmth).

Vascular permeability and increased vascular flow (secondary): The microvasculature becomes more permeable, and protein-rich fluid moves into the extravascular tissues. This causes the red cells in the flowing blood to become more concentrated, thereby increasing blood viscosity and slowing the circulation. These changes are reflected microscopically by numerous dilated small vessels packed with red blood cells, called stasis. (histamine mediated)

Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure intravascularly (i.e. outflow of protein makes water follow)

Vascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to collect and respond to the stimulus

The outcome of acute inflammation is either elimination of the noxious stimulus, followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation.

Question 7

What is erythema?

Answer 7

Superficial reddening of the skin, usually in patches, as a result of injury or irritation causing dilatation of the blood capillaries.

Question 8

What are some common stimuli for acute inflammation?

Answer 8

• Infections
• Trauma
• Tissue necrosis
• Foreign bodies
• Immune/hypersensitivity reactions- 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.

Question 9

What is margination?

Answer 9

stasis allows leukocytes to accumulate along the endothelial surface for diapedesis

As blood flows from capillaries into postcapillary venules, circulating cells are swept by laminar flow against the vessel wall. Because 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

Question 10

How does an Inflammasome work?

Answer 10

Binding of pathogenic bacteria causes activation of caspase-1 which activates IL-1beta. IL-1B then plays a role in leukocyte recruitment (important in type II diabetes and atherosclerosis)

Gain-of-function mutations in genes encoding some components of the inflammasome, one of which is called cryopyrin, 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.

Question 11

What is the difference between exudate and transudate?

Answer 11

Exudate- vascular permeability causes edema characterized by high cell density (may contain white and red cells)- usually with inflammation

Transudate- increased hydrostatic pressure caused by venous outflow obstruction (e..g congestive heart failure) caused edema fluid characterized by low protein content and few cells

Question 12

Vasodilation and vascular edema usually occurs at what point in a blood system?

Answer 12

postcapillary venules. Caused by contact of exposed collagen

Question 13

Several mechanisms may contribute to increased vascular permeability in acute inflammatory reactions. What are they?

Answer 13

Endothelial cell contraction leading to intercellular gaps in postcapillary venules

Endothelial injury

Increased transcytosisof proteins through channels formed by fusion of intracellular vesicles.

Leakage from new blood vessels, from tissue repair.

Question 14

What causes vasodilation?

Answer 14

Release of factors from leukocytes (histamine, kinins, prostaglandins, leukotrienes)

Question 15

What happens after vasodilation occurs?

Answer 15

leukocyte recruitment occurs

Question 16

How does leukocyte recruitment occur?

Answer 16

Macrophages send out chemokines to recruit them. Once they approach the site of infection, they begin to roll and attach to surface molecules on the endothelial surface. IL-1 will up regulate the expression of these molecules on the endothelial surface. Integrins cause stable adhesion and then diapedesis occurs via PECAM-1 (CD31)

Question 17

What is the purpose of alpha-1-antitrypsin?

Answer 17

keep the elastase from leukocytes in the lungs from going out of control and causing emphysema

Question 18

What is Chediak-Higashi?

Answer 18

AR

Characterized clinically by partial oculocutaneous albinism due to defects in melanin granules and recurrent pyogenic bacterial infections due to abnormalities in granulocytes.

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 affected, explaining the severe immunodeficiency typical
of the disorder.

All white blood cells contain abnormally giant granules.

You see normally segmented neutrophils with giant azurophilic granules so cytokines are not released properly

Question 19

What are the 4 morphologic patterns of acute inflammation?

Answer 19

Serous
Fibrinous
Suppurative
Ulcer

Question 20

Serous acute inflammation

Answer 20

characterized by the outpouring of a watery, relatively protein-poor fluid that, depending on the site of injury, derives either from the plasma or from the secretions of mesothelial cells lining the peritoneal, 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

Question 21

Fibrinous acute inflammation

Answer 21

Fibrinous inflammation occurs as a consequence of more severe injuries, resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier. Histologically, the accumulated 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, extensive fibrin-rich exudates may not be completely removed, and are replaced by an ingrowth of fibroblasts and blood vessels (organization), leading ultimately to scarring 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.

Question 22

What is an effusion?

Answer 22

fluid in a cavity

Question 23

What is an inflammasome?

Answer 23

a multi-protein cytoplasmic complex that recognizes products of dead cells, such as uric acid and extracellular ATP, as well as crystals and some microbial products via a sensor protein (a leucine-rich protein called NLRP3) and an adaptor. 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.

Question 24

In what cases would an inflammasome be activated?

Answer 24

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 antagonists are effective treatments in cases of gout that are resistant to conventional anti-inflammatory therapy. Recent studies have shown that cholesterol crystals and free fatty acids also activate the inflammasome, suggest- ing that IL-1 plays a role in common diseases such as atherosclerosis (associated with deposition of cholesterol crystals in vessel walls) and obesity-associated type 2 diabetes. This finding raises the possibility of treating these diseases by blocking IL-1.

Question 25

What mechanisms may contribute to increased vascular permeability in acute inflammatory reactions?

Answer 25

1) Endothelial cell contraction leading to intercellular gaps in postcapillary venules is the most common cause of increased vascular permeability. Endothelial cell contraction occurs rapidly after binding of histamine, bra- dykinin, leukotrienes, and many other mediators to specific receptors, and is usually short-lived (15 to 30 minutes). A slower and more prolonged retraction of endothelial cells, resulting from changes in the cytoskeleton, may be induced by cytokines such as tumor necrosis 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 results in vascular leakage by causing endothelial cell necrosis and detachment. Endothelial cells are damaged after severe injury such as with burns and some infections. In most cases, leakage begins immediately after the injury and persists for several hours (or days) until the damaged vessels are throm- bosed or repaired. Venules, capillaries, and arterioles can all be affected, depending on the site of the injury. 3) Increased transcytosis of proteins by way of an intracellular vesicular pathway augments venular permeability, especially after exposure to certain mediators such as vascular endothelial growth factor (VEGF). Transcytosis occurs through channels formed by fusion of intracel- lular vesicles. 4) Leakage from new blood vessels. 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 26

What happens to lymphatic vessels in response to acute inflammation?

Answer 26

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 lymphatics may transport the offending agent, contributing to its dissemination.

Question 27

T or F. 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.

Answer 27

T. Therefore, host defense mecha- nisms include checks and balances that ensure that leukocytes 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 (Chapter 3).

Question 28

Where is E-selectin (also called CD62E), expressed?; P-selectin (CD62P)?, L-selectin (CD62L)?

Answer 28

E=on endothelial cells P=present on platelets and endothelium L=on the surface of most leukocytes 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).

Question 29

What are Weibel-Palade bodies?

Answer 29

P-selectin is found primarily in intracellular Weibel-Palade bodies in platelets and endothelial cells. These also secrete vMF

Question 30

What causes up regulation of P-selectin on platelets and endothelial cells?

Answer 30

histamine and thrombin

Question 31

What causes up regulation of E-selectin and the ligand for L-selectin on platelets and endothelial cells?

Answer 31

Similarly, E-selectin and the ligand for L-selectin, which are not expressed on normal endothelium, are induced after stimulation by the cytokines IL-1 and TNF. These also up regulate ICAM via LFA-1 binding

Question 32

What is the molecule on leukocytes bind to P-selectin and E-selectin?

Answer 32

Sialyl–Lewis X–modified glycoprotein

Question 33

Integrins (e.g. LFA-1 on leukocytes and T cells) are usually expressed in low amounts as low affinity receptors and do not bind to ICAM-1 until what occurs? What happens when this occurs?

Answer 33

stimulation via chemokines. When the adherent leukocytes encounter the displayed chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, thus converting to a high- affinity form.

Question 34

Engagement of integrins to ICAMs on endothelial cells cause what to happen to leukocytes?

Answer 34

After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primar- ily by squeezing between cells at intercellular junctions. This extravasation of leukocytes, called diapedesis, occurs mainly in the venules of the systemic vasculature In addition, platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31), a cellular adhesion molecule expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium.

Question 35

What allow leukocytes to pass through the vascular basement membrane after they make it through the endothelial cell layers during extravasation?

Answer 35

collagenases

Question 36

What is chemotaxis?

Answer 36

After extravasating from the blood, leuko- cytes move toward sites of infection or injury along a chem-ical gradient by a process called chemotaxis Chemotactic molecules bind to specific cell surface receptors, which triggers the assembly of cytoskeletal con- tractile elements necessary for movement. Leukocytes move by extending pseudopods that anchor to the ECM and then pull the cell in the direction of the extension. 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.

Question 37

In most forms of acute inflammation, ____ predominate in the inflammatory infiltrate during the first _ to __ hours and are replaced by _____ in __ to __ hours

Answer 37

neutrophils; 6 to 24 | monocytes; 24 to 48

Question 38

Why are neutrophils commonly the first leukocytes to an inflammation site?

Answer 38

These cells are the most numerous leukocytes in the blood, they respond more rapidly to chemokines, and they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P- and E-selectins. In addition, after entering tissues, neutrophils are short-lived—they die by apoptosis and disappear within 24 to 48 hours—while monocytes survive longer. There are exceptions to this pattern of cellular infiltration, however.

Question 39

Exceptions to last slide?

Answer 39

In certain infections (e.g., those caused by Pseudomonas organisms), the cellular infiltrate is dominated by continuously recruited neutrophils for several days; in viral infections, lymphocytes may be the first cells to arrive; and in some hypersensitivity reactions, eosinophils may be the main cell type.

Question 40

What is the difference between Leukocyte-deficiency Type 1 and Type 2?

Answer 40

In leukocyte adhesion deficiency 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 deficiency type 2 (LAD-2) is caused by a defect in fucose metabolism resulting in the absence of sialyl–Lewis X, the oligosaccharide on leukocytes that binds to selectins on activated endothelium.

Question 41

What typically accompanies infection in those with CGD?

Answer 41

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.v

Question 42

Although the consequences of acute inflammation are modified by the nature and intensity of the injury, the site and tissue affected, and the ability of the host to mount a response, acute inflammation generally has one of three outcomes:

Answer 42

1) 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. 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. 2) 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. 3) 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. 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, a process that can significantly compromise function.

Question 43

Supportive (purulent) acute inflammation

Answer 43

These are manifested by the collection of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. Certain organisms (e.g., staphylococci) are more likely to induce such localized suppuration and are therefore referred to as pyogenic (pus-forming)

Question 44

What is an Abscess?

Answer 44

Abscesses are focal collections of pus that may be caused by seeding of pyogenic organisms 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.

Question 45

What is an Ulcer?

Answer 45

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. During the acute stage, there is intense polymorphonuclear infiltration and vascular dila- tion in the margins of the defect. With chronicity, the margins and base of the ulcer develop scarring with accu- mulation of lymphocytes, macrophages, and plasma cells.