2. Acute inflammation - vascular and cellular phases

Question 1

what is acute inflammation?

Answer 1

Stereotyped, immediate (min/hrs/few days) response of vascularised living tissue to injury, initiated to limit tissue damage.

Question 2

what is the purpose of acute inflammation?

Answer 2

Deliver defensive materials (blood cells and fluid) to a site of injury to:

i) protect body against infection (esp bacterial infection)
ii) clear damaged tissue
iii) initiate tissue repair

Question 3

name the main causes of acute inflammation.

Answer 3

1. infections (bacterial, viral, parasitic) and microbial toxins
2. immune (hypersensitivity) reactions - acute phase
3. tissue necrosis (any cause)
4. physical agents - e.g. trauma (blunt and penetrating), thermal (burns/frostbite), radiation
5. chemical agents
6. foreign bodies (splinters, dust, sutures)

Question 4

name the main clinical signs of acute inflammation.

Answer 4

1. rubor (redness)
2. calor (heat)
3. tumor (swelling)
4. dolor (pain)
5. functio laesa

Question 5

what are the 2 main phases of acute inflammation?

Answer 5

1. vascular phase
   - changes in blood flow (transient vasoconstriction followed by vasodilation)
   - exudation of fluid into tissues
2. cellular phase
   - infiltration of inflammatory cells

Question 6

explain why rubor, calor and tumour are clinical signs of AI.

Answer 6

1. arterioles and then capillaries dilate… increased blood flow (RUBOR and CALOR)…
2. increased capillary pressure and increased permeability of capillaries and venules…
3. exudation of protein-rich fluid into tissues (TUMOR).

Question 7

how does fluid exudation into tissues lead to blood stasis?

Answer 7

exudation into tissues increases haematocrit (conc. of RBCs) in venules… increases blood viscosity and resistance to blood flow… slowing of circulation - stasis.

Question 8

Explain the process of fluid exudation in AI in terms of Starling Forces.

Answer 8

Fluid flow across vessel walls is determined by the balance of hydrostatic and colloid osmotic pressure in plasma and interstitial fluid. In AI:

• arteriolar dilation… increased plasma hydrostatic pressure
• increased permeability of vessel walls… loss of proteins into interstitium… increased interstitial colloid osmotic pressure

Cause net flow of fluid out of vessels - oedema

Question 9

What is the difference between an exudate and a transudate?

Answer 9

• transudate = lost fluid has same protein content as plasma - due to hydrostatic pressure imbalance only (e.g. cardiac failure or venous flow obstruction), no vessel wall gaps caused by endothelial cell contraction
• exudate = lost fluid has higher protein content than plasma - due to inflammation

Question 10

What types of plasma proteins are found in exudate?

Answer 10

1. opsonins - enhance phagocytosis of foreign material, inc. complement and antibodies
2. fibrin - creates meshwork that localises inflammatory/immune factors (crucial at serosal surfaces which have massive surface area)

Question 11

Which type of chemical mediator is the 1st to be released in AI?

Answer 11

Vasoactive amines inc. histamine and serotonin - within 1/2hr

Are available immediately from preformed supplies and are already present within cells in tissues and platelets.

Question 12

Which cells release histamine and how is this stimulated?

Answer 12

• Stored and released from granules of mast cells, basophils and platelets.
• In response to many stimuli, e.g. physical damage, immune reactions, complement (C3a, C5a) and IL-1

Question 13

What is the function of histamine in AI?

Answer 13

1. pain
2. vascular dilation
3. transient increase in vascular permeability - causes endothelial cells to contract and pull apart, creating gaps through which plasma proteins can pass - allows exudation

Question 14

What is the function of prostaglandin in AI?

Answer 14

1. vasodilation
2. increased skin sensitivity to pain
3. fever

Question 15

How is prostaglandin produced?

Answer 15

from cell membrane phospholipids (arachidonic acid)

Question 16

How do aspirin and NSAIDs reduce pain and swelling?

Answer 16

block production of prostaglandin by inhibiting cyclo-oxygenase, the enzyme that produces prostaglandin from arachidonic acid

Question 17

What are the different mechanisms mediating vascular leakage?

Answer 17

1. Chemical mediators:
   - histamine, serotonin and leukotrienes promote endothelial cell contraction
   - cytokines IL-1 and TNF promote cytoskeletal reorganisation
   - bradykinin
   - C3a, C4a and C5a
2. Direct injury of vessel wall, e.g. toxic chemicals, burns
3. Leukocyte-dependent injury: release toxic oxygen species and enzymes
4. VEGF stimulates increased transcytosis (channels across endothelial cytoplasm)

Question 18

The presence of which cell type defines AI?

Answer 18

neutrophils

Question 19

How are neutrophils summoned to the place of injury?Give examples of the molecules involved.

Answer 19

Chemotaxis = movement (~30 um/min) up concentration gradient of a chemical attractant - chemotaxin. E.g.

• bacterial endotoxin: lipopolysaccharide on outer membrane of GNB
• clotted blood: thrombin and fibrin degradation protducts (produced by plasmin-mediated clot breakdown)
• C3a, C4a and esp. C5a
• leukocyte-produced chemotaxins, most powerful of which is leukotriene B4

Question 20

How does binding to a chemotaxin activate neutrophils?

Answer 20

Within 5 sec of chemotaxin binding to cell surface receptor, calcium and sodium ions rush influx into cell… cells swells and reorganises cytoskeleton into roughly triangular shape pointing in direction of chemotatic stimulus… within 5-10 sec, cell sends out pseudopodia.

Activated cells are stickier than normal cells.

Question 21

Explain the process of tissue infiltration by neutrophils.

Answer 21

1. Margination: stasis causes neutrophils to line up at the edge of blood vessels along the endothelium.
2. Rolling: neutrophils roll along endothelium, intermittently sticking to it via receptors binding to selectins.
3. Adhesion: neutrophils adhere firmly to vessel wall by receptors binding to integrins (e.g. ICAM-1, intercellular adhesion molecule 1).
4. Emigration of neutrophils through vessel wall.

No. of selectins and activation of integrins are increased by inflammatory mediators and chemotaxins.

Question 22

How do neutrophils cross the blood vessel wall into tissues?

Answer 22

Via diapedesis (3-9 min):

1. relaxation of inter-endothelial cell junctions and extension of pseudopodia
2. production of collagenase and digestion of vascular basement membrane
3. movement along collagen fibres of other tissue structures once in extravascular space

Question 23

How do neutrophils recognise bacteria?

Answer 23

1. Via opsonins = plasma proteins that bind the MO to facilitate recogntion. e.g.
   - IgG antibody - neutrophil binds Fc
   - C3b
2. In absence of opsonins, neutrophils recognises MO surface antigens

Question 24

Describe the process of phagocytosis.

Answer 24

1. Binding of neutrophil receptors to particle.
2. Cytoskeletal changes as membrane surrounds particle, forming a phagosome.
3. Phagolyosome fusion: cell’s granules fuse with phagosome and release bactericidal enzymes - degranulation.

Question 25

What are the 2 main killing mechanisms used by neutrophils?

Answer 25

1. O2-dependent (respiratory burst)
   - release of ROS (hydrogen peroxide, superoxide anion and hydroxyl) into the phagosome
2. O2-independent (release of enzymes)
   - lysozyme, proteases, phospholipases and nucleases
   - bactericidal permeability increasing protein (BPI)
   - cationic proteins (‘defensins’)

Question 26

Why can neutrophils damage host tissues as well as pathogens?

Answer 26

Degranulation begins to occur before the particle is completely enclosed - some toxic metabolites leak out into surrounding tissue spaces.

Question 27

Name the chemical mediators (and their sources) mediating vasodilation.

Answer 27

1. histamine and serotonin (mast cells, basophils and platelets)
2. prostaglandins (many cells)

Question 28

Name the chemical mediators (and their sources) mediating increased vascular permeability.

Answer 28

1. histamine and serotonin (mast cells, basophils and platelets)
2. bradykinin (plasma precursor kininogen)
3. leukotrienes (arachidonic acid of leucocytes)

Question 29

Name the chemical mediators (and their sources) mediating chemotaxis.

Answer 29

1. leukotriene B4 (arachidonic acid of leucocytes)
2. chemokines (leucocytes and other cells)
3. bacterial products
4. C5a and C3a (complement precursors)

Question 30

Name the chemical mediators (and their sources) mediating phagocytosis.

Answer 30

C3b

Question 31

Name the chemical mediators (and their sources) mediating pain.

Answer 31

1. bradykinin (plasma precursor kininogen)
2. prostaglandins (many cells)
3. histamine (mast cells, basophils and platelets)

Question 32

Describe the production and function of bradykinin (vasoactive peptide).

Answer 32

• Circulates in blood as part of larger molecule kininogen… cleaved by kallikrein enzyme.
• Produced within ~1min.
• Similar functions to histamine: increased vascular permeability, vasodilation and burning pain.

Question 33

Describe the production of chemical mediators from phospholipids.

Answer 33

1. Phospholipase A2 produces arachidonic acid from plasma membrane phospholipids.
2. Arachidonic acid is metabolised by:
   - cyclo-oxygenase to produce prostaglandin (most cells)
   - lipooxygenase to produce leucotrienes (only in leucocytes)

Question 34

What are cytokines and chemokines?

Answer 34

• Cytokines = polypeptides produced by many cells that act as intercellular messengers. E.g. interleukins, TNFa, interferons
• Chemokines = type of cytokine involved in chemotaxis. E.g. leukotriene B4.

Many cytokines produced by macrophages and appear in hrs following injury.

Question 35

What are the effects of endotoxin release by GNB?

Answer 35

• Release into tissues = inflammation

- Release into blood = septic shock (activation of numerous inflammatory mechanisms at once)

Question 36

How do corticosteroids inhibit inflammation?

Answer 36

inhibit phospholipase A2, preventing production of arachidonic acid

Question 37

How does exudation of fluid combat injury?

Answer 37

1. delivers defensive plasma proteins to the site of injury: immunoglobulins, inflammatory mediators, fibrinogen
2. increases lymphatic drainage… any microorganisms/antigens are presented to immune system within lymph nodes
3. dilutes toxins

Question 38

How does cell infiltration combat injury?

Answer 38

removes pathogenic organisms and necrotic debris

Question 39

How does vasodilation combat injury?

Answer 39

1. Increases delivery of inflammatory cells

2. Increases temperature

Question 40

How does pain and loss of function combat injury?

Answer 40

enforces rest, reduces chance of further traumatic damage