Acute Inflammation (Session 2) Flashcards
(107 cards)
1
Q
What is inflammation?
A
Inflammation is a rapid response to injury of vascularised living tissue.
2
Q
1) What is the purpose of inflammation?
2) What does inflammation aim to do?
A
1) To deliver defensive materials (white blood cells and fluid containing plasma proteins) to a site of injury.
2) to protect the body against infection, particularly bacterial infection, and to clear damaged tissue and initiate tissue repair.
3
Q
1) How long does acute inflammation take to evolve?
2) Give 2 words to describe acute inflammation
A
1) Over hours or days
2) Innate and stereotyped.
4
Q
How long does chronic inflammation take to evolve?
A
Over weeks, months or even years;
5
Q
What suffix is used to indicate inflammation of an organ or tissue, and give an example
A
–itis
e.g., appendicitis = inflammation of the appendix.
6
Q
In inflammation, why do defensive cells, fluid and proteins need to be delivered?
A
as local defences are not adequate to protect against infection
7
Q
1) How do the defensive agents circulate in the blood?
2) What happens when they are needed?
3) Where do defensive agents leave the blood vessels?
4) How must this be accomplished?
A
1) Most, but not all, of the defensive agents circulate in the blood in inactive form.
2) they are delivered and activated.
3) at the site of the injury.
4) without interrupting the blood flow which must continue on to other tissues.
8
Q
1) Describe the process of the passage of leucocytes and fluids (which contains plasma proteins) out of the blood
2) What is it controlled by?
3) How long does it take to deliver fluids to the site of injury?
4) How long does it take to deliver leukocytes to the site of injury?
A
1)complex process
2) chemical messages which are called chemical mediators or mediators of inflammation.
3) delivered to the site of injury first in seconds
4) leucocytes take longer (minutes) because they can’t just pour out of the vessels.
9
Q
Give 6 causes of acute inflammation
A
- Foreign bodies (splinters, dirt, sutures)
- Immune reactions
- Infections (bacterial, viral, parasitic) and microbial toxins
- Tissue necrosis (any cause)
- Trauma (blunt and penetrating)
- Physical and chemical agents (e.g., thermal injury, e.g., burns or frostbite, irradiation,
environmental chemicals).
10
Q
Give 6 clinical signs of inflammation
A
- Rubor = redness
- Calor = heat
- Tumour = swelling
- Dolor = pain
- Loss of function – this enforces rest and reduces the chance of further damage (this sign was
added more recently by Virchow).
11
Q
1) What is the first thing that happens when inflammation occurs?
A
a brief moment of vasoconstriction which is swiftly followed by vasodilatation of the arterioles (small arteries).
12
Q
What brings about vasodilation of the arterioles in inflammation?
A
Vasoactive mediators such as histamine (many other mediators that also cause vasodilatation).
13
Q
1) What happens during arteriole dilation?
2) Why does vasodilation in arterioles occur in inflammation?
A
- Flow accelerates in the capillaries and capillary
pressure rises.
2) These changes increase the delivery of fluid and leucocytes to the area of injury.
14
Q
1) What is the second step that occurs in inflammation? (following the dilation of arterioles)
2) What does this cause ?
A
1) Walls of the venules become leaky and plasma can escape through tiny gaps between endothelial cells
2)
- An increased haematocrit within the venules and increased resistance to blood flow within them.
- This stops blood outflow from the area of injury and there is increased pressure upstream.
- The lumens of the upstream vessels thus dilate and blood flow slows down.
- The increased pressure within the vessels results in greater exudation of fluid into the tissue spaces thus delivering plasma proteins to the site of injury.
15
Q
What is a really important substance in the early changes in inflammation?
A
Histamine
16
Q
1) What group does histamine belong to?
2) Name another substance than belongs to this group
A
1) a group of chemical mediators called vasoactive amines
2) Serotonin
17
Q
What are usually the first mediators to appear during inflammation?
A
Vasoactiveamines
18
Q
Many mediators are not available immediately from performed supplies during inflammation.
Name some mediators that are already present within cells in the tissues and platelets
A
Histamine and serotonin
19
Q
1) Where is histamine stored before release?
2) Where is serotonin stored before release?
A
1) in the granules of mast cells, basophils and platelets
2) In the granules of platelets
20
Q
Name some stimuli that can warrant the release of histamine (3)
A
- Physical damage
- Immune reactions
- Complement components
21
Q
What does histamine cause in acute inflammation?
What does serotonin cause?
A
1)
- Produces pain
- Arteriolar dilatation
- Venular leakage (increased permeability).
2) The vascular effects are similar to those of histamine
22
Q
Why does fluid leakage occur in acute inflammation?
A
- The fluid leakage occurs as histamine causes endothelial cells to contract and pull apart.
- This creates gaps through which plasma proteins can pass.
23
Q
What are prostaglandins?
A
substances produced in inflammation from cell membrane phospholipids
24
Q
What do prostaglandins do? (3)
A
- Cause vasodilation
- Make the skin more sensitive to pain
- Cause fever
25
1) How can the production of prostaglandins be blocked?
2) How does this work?
1) By aspirin and NSAIDs
2) They inhibit cyclo-oxygenase, the enzyme that produces prostaglandins from arachidonic acid).
26
What effect to aspirin and NSAIDs have on the body?
How?
Reduce pain and swelling by blocking the production of prostaglandins
27
Name 2 other substances that have vasoactive properties
leukotrienes and bradykinin
28
What are the effects of bradykinin?
produces pain and increased vascular permeability.
29
1) How does acute inflammation throw off the equilibrium of fluid exchange in the microcirculation?
2) Which law describes the forces involved in this equilibrium?
1)
- In acute inflammation, arterioles, under the direction of chemical mediators, dilate and venules, also under the direction of chemical mediators, become leaky as the endothelial cells contract and create gaps.
2) Starling's law
30
What forces are involved in the equilibrium of fluid exchange?
* Capillary pressure
* Interstitial free fluid pressure
* Plasma colloid osmotic pressure
* Interstitial fluid colloid osmotic pressure.
31
1) Describe the usual way that capillaries and venues act and the force involved
2) In the usual case, what is the main force driving fluid out of the vessels?
3) What is the main force driving fluid back into the blood?
4) Describe how this changes in acute inflammation
- In the usual state, endothelium of the capillaries and venules acts as a semipermeable membrane, allowing escape of water and electrolytes but retaining plasma proteins hence the exchanges between the blood and tissue spaces depends on the four forces listed above.
2) The hydrostatic pressure of the blood
3) The colloidal osmotic pressure of the plasma proteins.
4) In acute inflammation:
* The semipermeable membrane becomes leaky
* The main force driving the fluid out of the vessels is increased (arterioles dilate increasing
capillary pressure)
* The main force driving fluid back into the blood is reduced as plasma proteins escape into the
tissue spaces raising the osmotic pressure there so that it roughly equals that of blood.
32
In acute inflammation, the balance of starling's forces is altered. Describe what this results in
- The net flow of fluid (with its plasma proteins) out of the vessels into the tissue spaces.
33
Describe 2 main functions of (the abundant) tissue fluid/exudate
- Delivering plasma proteins to the site of injury
- Excess tissue fluid drains from the tissues in the lymphatics taking with it micro-organisms and antigens which are thus presented to the immune system within the lymph nodes.
34
Name and describe the 3 defensive proteins found in tissue fluid (exudate)
* Opsonins – which coat foreign materials and make them easy to phagocytose.
* Complement – a group of proteins that are assembled locally to produce a bacteria- perforating structure (see below).
* Antibodies – bind to the surface of micro-organisms and also act as opsonins.
35
1) Name and describe the 2 types of tissue fluid
2) What kind of tissue fluid develops in inflammation?
1)
- Exudate (protein rich)
- Transudate (protein poor)
2) Exudate
36
1) What is a transudate?
2) What does it occur with?
3) Give an example of a condition that it is seen in
1) an ultrafiltrate of plasma
2) occurs with normal vessels (i.e., there are no gaps caused by endothelial cell contraction).
3) conditions such as heart failure when there is increased capillary hydrostatic pressure.
37
List some chemical mediators that induce vascular leakage and state where they are found (4)
- Histamine (found in mast cells and platelets)
- Serotonin (found in mast cells and platelets)
- Bradykinin (formed from a plasma precursor)
- The complement components C3a, C4a and C5a (also formed from plasma precursors).
38
What is the primary type of leucocyte involved in acute inflammation?
Neutophil
39
1) Where are neutrophils only found, normally?
2) What does their presence in tissue indicate?
1) only found in the blood and bone marrow
2) their presence in the tissue indicates invasion by bacteria or some other parasite and/or tissue injury.
40
1) What is the lifespan of neutrophils?
2) What kind of cells are they?
1) 12- 20 hours and
2) an end cell - they cannot multiply.
41
What does each neutrophil contain?
about 2,000 granules and these contain bactericidal substances.
42
How do neutrophils act?
Neutrophils escape from blood vessels into tissue spaces in response to chemical ‘calls’ originating from bacteria, injured cells or other inflammatory cells.
43
To capture and kill a bacterium in the tissue space, a neutrophil must:
1. Be summoned to the place of injury = chemotaxis
2. Switch to a higher metabolic level = activation
3. Stick to the endothelial surface = margination
4. Crawl through the endothelium = diapedesis
5. Recognise the bacterium and attach to it = recognition-attachment
6. Engulf the bacterium = phagocytosis.
44
What is chemotaxis?
Chemotaxis is the directional movement towards a chemical attractant (chemotaxin).
45
At what rate do neutrophils move up a chemotactic gradient?
at approximately 30 μm/min = approximately 2 mm/hour.
46
Give examples of chemotaxins (4)
- Bacterial products
- Injured tissues
- Substances produced by leucocytes
- Spilled blood.
47
Give an example of a bacterial chemotaxin
Endotoxin
48
What is an endotoxin?
a lipopolysaccharide from the outer membrane of gram negative bacteria.
49
What kind of blood is chemotactic and which kind of blood isn't?
Fresh blood isn’t chemotactic but clotted blood is.
50
Why is clotted blood chemotactic?
Both thrombin and FDPs are chemotactic, therefore clotting blood is chemotactic.
51
1) What does activation of complement release?
2) Describe the chemotactic nature of these
1)fragments of C3, C4 and C5 called C3a, C4a and C5a.
2) All of these, but especially C5a are chemotactic.
52
1) What can leukocytes produce?
2) Which is the most powerful?
1) can produce chemotaxins
2) The most powerful of which is leukotriene B4.
53
Describe what happens within 5 seconds of the chemotaxin binding to cell surface receptors
2) Compare activated cells to normal cells
- Calcium and sodium ions rush into the cell, it swells and reorganises its cytoskeleton assuming a roughly triangular shape pointing in the direction of the chemotactic stimulus.
- Within 5-10 seconds the cell sends out pseudopodia.
2) Activated cells are stickier than normal cells.
54
What is margination?
The process whereby leucocytes assume marginal positions in the vessels.
55
Describe the process of margination, rolling and adhesion
- Margination is the process whereby leucocytes assume marginal positions in the vessels.
- Leucocytes stick to the walls of venules as they heed the chemotactic ‘call’.
- They roll along the wall but then become ‘trapped’ (adhesion), stop and crawl out of the vessel.
- Leucocytes are trapped when their receptors bind to adhesion molecules (called selectins and integrins) on the endothelium.
- When the leucocytes roll along the endothelium they are binding to selectins, when they adhere and stick firmly they are binding to integrins such as ICAM-1 (intercellular adhesion molecule-1).
- The number of selectins and the activation of integrins are increased by inflammatory mediators and chemotaxins.
56
Describe the process of diapedesis
- Leucocytes ‘dig’ their way out of the venules, they don’t use the endothelial gaps through which the exudate escapes.
- They produce collagenase which digests the basement membrane.
- Diapedesis takes a number of minutes, in the order of 3-9 minutes.
- Once in the extravascular space the leucocytes move towards their target by pulling themselves along collagen fibres of other tissue structures.
57
What are opsonins?
substances which make it easier for phagocytes to recognise targets, attach to them and then phagocytise them
58
What kind of substances are opsonins
Plasma proteins
59
Name and describe 2 examples of opsonins
* IgG antibody – this is the most important opsonin but it will not be present when a bacterium is encountered for the first time.
* C3b fragment of complement – this is released when complement is activated.
60
What happens if opsonins are not present?
then the phagocyte recognises microbial surface antigens.
61
Describe the processs of phagocytosis
- During phagocytosis the membrane of the phagocyte forms a crater shape around the particle that is to be phagocytised.
- This crater then develops into a cup which surrounds the particle. The edges of the cup come together and the apposed plasma membranes fuse.
- The particle is then within an intracellular vacuole which is called a phagosome.
- The phagosome then proceeds to digest the particle.
- The cell’s granules move towards the phagosome, fuse with it and inject their bactericidal substances into it.
- This process is called degranulation.
- Degranulation begins to occur before the particle is completely enclosed and some of the bactericidal enzymes leak out into the surrounding tissue spaces.
62
Why can phagocytosis result in local tissue injury?
What kills a bacterium can also kill a cell of the body and this ‘early’ degranulation results in local tissue injury
63
as well as phagocytising pathogenic organisms, what else do nenutophills do?
Remove necrotic cell debris
64
What are the 2 mechanisms that phagocytise organisms can be killed?
- Oxygen-dependent
- Oxygen-independent
65
Describe the oxygen dependant pathway of killing organisms that have been phagocytised
using oxygen derived free radicals (hydrogen peroxide (H2O2), superoxide anion (O2-) and hydroxyl (OH.)) which are released into the phagosome. This
mechanism of killing is called the oxygen burst or respiratory burst.
66
Describe the oxygen independant pathway of killing organisms that have been phagocytised
using enzymes, e.g., proteases, phospholipases, nucleases and
lysozyme.
67
What is a mediator?
any molecule that is produced in a focus of inflammation and modulates the inflammatory response in some way.
68
List some common responses to mediators
- Motion (contraction or relaxation of vascular smooth muscle cells, contraction of venular endothelial cells, movement along a chemotactic gradient and phagocytosis by neutrophils)
- Secretion
69
1) What does every mediator have?
2) Why is this important?
1) Inhibitors
2) otherwise inflammation would be on-going and would spread around the body.
70
Describe what limits the duration of inflammation
1) Every mediator has inhibitors, otherwise inflammation would be on-going and would spread around the body.
2) The duration of inflammation is also limited due to the fact that mediators have short lives – seconds to minutes – and their effects last minutes to hours (long-standing inflammation is sustained by continued production of mediators).
71
What are endogenous mediators supplied by?
- the plasma
- leucocytes
- local tissue
72
Name the 7 groups of mediators
- Vasoactive amines
- Vasoactive peptides
- Complement components
- Clotting and fibrinolytic cascades
- Mediators derived from phospholipids
- Cytokines and chemokines
- Exogenous mediators of inflammation,
73
Give 2 examples of vasoactive amines
histamine and serotonin
74
Give an example of a vasoactive peptide and describe what it does
e.g., bradykinin. Bradykinin circulates in the blood as part of the larger
molecule kininogen. The enzyme kallikrein cleaves kininogen and bradykinin is produced. Its effects are very similar to those of histamine (increased vascular permeability, vasodilatation and burning pain) and it is produced quickly, within a minute or so.
75
Give 2 examples of complement components and describe what it does
e.g., C3a, C5a. The function of complement is to form a tube (called the membrane attack complex) which punches holes in bacteria thus causing them to die. It circulates in the blood as a number of disassembled proteins. When it assembles into its tube structure it generates, as by products , some powerful inflammatory mediators (C3a, C5a) and also the opsonin C3b.
76
Describe what clotting an fibrinolytic cascades do
both these processes generate inflammatory mediators
77
Give 3 examples of mediators derived from phospholipids and describe what it does
prostaglandins, thromboxanes and leukotrienes. Arachidonic acid is produced by the action of phospholipase A2 (inhibited by corticosteroids) on plasma membrane phospholipids. Arachidonic acid can then be metabolised by cyclo-
oxygenase (which produces prostaglandins and thromboxanes) (inhibited by aspirin and NSAIDs)orlipoxygenase(whichproducesleukotrienes). Prostaglandins(ofwhichprostacyclin is one) can be produced by most cells. Leukotrienes are produced only by leucocytes, hence their name. Leukotriene B4 is a very powerful chemotactic agent.
78
Give 2 examples of cytokines and chemokine and describe what it does
e.g., interleukins, tumour necrosis factor (TNF), interferons. Cytokines are polypeptides that are produced by many cells and act as messengers between cells. Chemokines (short for chemotactic cytokines) are a group of cytokines which are involved in chemotaxis. Many cytokines are produced by macrophages and they start to appear in the hours following injury. They have both local and systemic effects. For example, TNF (which is also called cachectin) is largely responsible for cachexia seen in association with malignancy.
79
Give 2 examples of exogenous mediators of inflammation and describe what it does
e.g., endotoxin produced by gram negative bacteria. When endotoxin is released into tissue it causes inflammation, however if it is released into the blood it activates numerous inflammatory mechanisms at once and this results in septic shock.
80
State and describe the main roles and main sources of inflammatory mediators
* Vasodilatation – histamine and serotonin (from mast cells and platelets), prostaglandins (from many cells).
* Increased vascular permeability – histamine and serotonin (from mast cells and platelets), bradykinin (from the plasma precursor kininogen).
* Chemotaxis – leukotriene B4 (from leucocytes), C5a and C3a (from complement plasma precursors), chemokines (from leucocytes and other cells), bacterial products (from bacterial metabolism).
* Phagocytosis – C3b (from complement plasma precursor).
* Pain – bradykinin (from the plasma precursor kininogen), prostaglandins (from many cells).
81
Describe 4 local complications of acute inflammation
* Damage to normal tissue – secondary to substances produced by neutrophils and released
during the process of phagocytosis.
* Obstruction of tubes, such as the intestine or Fallopian tubes, and compression of vital
structures – secondary to the swelling produced by the inflammatory exudate.
* Loss of fluid – in tissue spaces as fluid accumulates the tissue pressure increases until it reaches a level that prevents further exudation. However, fluid can continuously leak from a surface wound. For this reason, extensive skin wounds, such as burns, result in the loss of
very large amounts of fluid.
* Pain and loss of function.
82
Although produced locally, what are inflammatory mediators able to do?
can enter the blood stream in significant amounts and have systemic effects.
83
How quickly can the systemic effects of acute inflammation be seen?
Within 1 day
84
Name the 4 main systemic effects of acute inflation
- Fever
- Leucocytosis
- The acute phase respone
- Shock
85
Describe why fever occurs as as systemic effect in acute inflammation
- Fever occurs when the thermostat of the body (situated in the anterior hypothalamus) is switched to a higher setting.
- Macrophages when they are stimulated to do so by exogenous (bacterial) pyrogens (particularly endotoxin) produce pyrogenic cytokines, e.g., TNF, interleukin-1.
- These cytokines cause an increase in synthesis of prostaglandin E2 within the anterior hypothalamus.
86
What can reduce fever?
Describe how
As aspirin inhibits cyclo-oxygenase (the enzyme which produces prostaglandins) it reduces fever.
87
1) Why can fever be useful?
2) Why else is fever beneficial?
1) Fever can be useful as some bacteria can’t survive at high temperatures (40-41oC)
2) Inflammation has been demonstrated to be more effective at higher temperatures
88
Describe why leucocytosis occurs as a systemic effect of acute inflammation
In leucocytosis the number of circulating leucocytes increases.
Neutrophilia is seen during bacterial infection. Macrophages and endothelial cells in injured tissues produce colony stimulating factors and these stimulate the bone marrow to produce more neutrophils.
89
What is the acute phase response?
a change in the levels of some plasma proteins that is seen because the liver changes its pattern of protein synthesis.
90
How soon after injury does the acute phase response occur?
within hours of injury.
91
describe the proteins inducing in the acute phase response
Some proteins are produced in smaller amounts by the liver, e.g., albumin, and others are produced in larger amounts, e.g., fibrinogen (needed for blood coagulation), ceruloplasmin (a free radical scavenger), C3 (a protein of the complement system), alpha-1 antitrypsin (a protease inhibitor), C-reactive protein (CRP, an opsonin).
92
What is responsible for the production of the acute phase response?
Cytokines released during inflammation
93
What symptoms can be triggered due to the acute phase response?
What kind of injury are these symptoms triggered?
sleepiness and lack of appetite
- seen in serious injury
94
Describe how shock results
If bacterial products or inflammatory mediators spread around the body in the blood stream inflammation can occur throughout the body. This results in shock.
95
What is shock?
a dramatic drop in blood pressure due to widespread vasodilatation and increase in vascular permeability with resultant fluid exudation. It is often fatal.
96
1) What happens as the triggers of inflammation are removed?
2) What allows this to happen?
3) What features of mediators allows this to happen?
1)
- Normal vascular permeability returns
- There is cessation of emigration of neutrophils
- Resolution of acute inflammation begins.
2) Mediators of inflammation
3)
- Have short half-lives
- Are degraded after release
- Are produced in quick bursts
- Present only as long as the stimulus persists.
97
Describe what happens in the resolution of acute inflammation
The exudate is reabsorbed into the venules or is drained away in the lymphatics, fibrin is degraded and neutrophils undergo apoptosis and are phagocytised along with necrotic debris by macrophages. If the damaged parenchymal cells can regenerate then the tissue will return to normal, however if regeneration cannot occur or damage has been extensive a fibrous scar will form (this process will be discussed in detail in the sessions on chronic inflammation and healing and repair).
98
Name the 4 types of exudate that are seen in inflammation that you should be aware of
- pus/abcess
- haemorragic exudate
- Serous exudate
- Fibrinous exudate
99
Describe pus/abcess
In an abscess the exudate is creamy/white as it is rich in neutrophils. Such an exudate is typical of infections by chemotactic bacteria.
100
Describe haemorragic exudate
A haemorrhagic exudate contains enough red blood cells to appear bloody to the naked eye. It indicates that as well as inflammation significant vascular damage has also occurred. It is seen in destructive infections or when the exudate is a result of infiltration by a malignant tumour.
101
Describe serous exudate
Serous exudates contain plasma proteins but few leucocytes suggesting that there is no infection by micro-organisms. They are clear and are seen typically in blisters, e.g., after a mild burn. Note serous exudates differ from transudates because they contain plasma proteins and they differ from plasma because they don’t contain fibrinogen. NB. A seroma is a tissue space filled with clear, sterile fluid that occurs as a post-operative complication.
102
Describe Fibrinous exudate
In a fibrinous exudate there is significant deposition of fibrin (i.e., a blood clot without the red blood cells). When fibrinous exudates occur in the pericardial or pleural spaces the fibrin that is deposited means that the serosal surfaces no longer slide smoothly over each other. This results in friction between the serosal surfaces which can be heard as a rubbing sound.
103
Give 5 clinical examples of acute inflammation
- Bacterial meningitis
- Lobar pneumonia
- Ascending cholangitis
- Liver abscess
- Acute appendicitis.
104
Name 3 disorders of acute inflammation
Hereditary angio-oedema
Alpha-1 antitrypsin deficiency
Chronic granulomatous disease
105
1) What is Hereditary angio-oedema?
2) Describe the symptoms of it
3) What is there usually a history of and why?
1) an extremely rare autosomal dominant condition in which sufferers have an inherited deficiency of C1-esterase inhibitor (a component of the compliment system).
2) Patients have attacks of non-itchy cutaneous angio-oedema (rapid oedema of the dermis, subcutaneous tissue, mucosa and submucosal tissues). They also experience recurrent abdominal pain which is due to intestinal oedema.
3)There is often a family history of sudden death which is due to laryngeal involvement.
106
1) What is Alpha-1 antitrypsin deficiency?
2) What do patients with this disorder develop and why?
3) What disease also occurs and why?
4) What does this cause?
1) This is an autosomal recessive disorder with varying levels of severity in which there are low levels of alpha-1 antitrypsin, a protease inhibitor which deactivates enzymes released from neutrophils at the site of inflammation.
2) develop emphysema as proteases released by neutrophils within the lung act unchecked and destroy normal parenchymal tissue.
3) Liver disease also occurs as the hepatocytes produce an abnormal
version of the protein which is incorrectly folded. It polymerises and cannot be exported from the endoplasmic reticulum.
4) This causes hepatocyte damage and eventually cirrhosis.
107
1) What is Chronic granulomatous disease?
2) What happens in this disease?
3) What can be seen in the first year of life?
4) What other symptoms do you get?
1) In this genetic condition phagocytes are unable to generate the free radical superoxide.
2)Bacteria are phagocytised but the phagocytes cannot kill them as they can’t generate an oxygen burst.
3) Many chronic infections
4) Numerous granulomas (these will be described in the next session on chronic inflammation) and abscesses affecting the skin, lymph nodes, and sometimes the lung, liver and bones occur, however they are ineffective at eliminating the infectious agents.
