Flashcards in 2. Acute inflammation - vascular and cellular phases Deck (40)
what is acute inflammation?
Stereotyped, immediate (min/hrs/few days) response of vascularised living tissue to injury, initiated to limit tissue damage.
what is the purpose of acute inflammation?
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
name the main causes of acute inflammation.
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)
name the main clinical signs of acute inflammation.
1. rubor (redness)
2. calor (heat)
3. tumor (swelling)
4. dolor (pain)
5. functio laesa
what are the 2 main phases of acute inflammation?
1. vascular phase
- changes in blood flow (transient vasoconstriction followed by vasodilation)
- exudation of fluid into tissues
2. cellular phase
-infiltration of inflammatory cells
explain why rubor, calor and tumour are clinical signs of AI.
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).
how does fluid exudation into tissues lead to blood stasis?
exudation into tissues increases haematocrit (conc. of RBCs) in venules... increases blood viscosity and resistance to blood flow... slowing of circulation - stasis.
Explain the process of fluid exudation in AI in terms of Starling Forces.
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
What is the difference between an exudate and a transudate?
- 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
What types of plasma proteins are found in exudate?
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)
Which type of chemical mediator is the 1st to be released in AI?
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.
Which cells release histamine and how is this stimulated?
- 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
What is the function of histamine in AI?
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
What is the function of prostaglandin in AI?
2. increased skin sensitivity to pain
How is prostaglandin produced?
from cell membrane phospholipids (arachidonic acid)
How do aspirin and NSAIDs reduce pain and swelling?
block production of prostaglandin by inhibiting cyclo-oxygenase, the enzyme that produces prostaglandin from arachidonic acid
What are the different mechanisms mediating vascular leakage?
1. Chemical mediators:
- histamine, serotonin and leukotrienes promote endothelial cell contraction
- cytokines IL-1 and TNF promote cytoskeletal reorganisation
- 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)
The presence of which cell type defines AI?
How are neutrophils summoned to the place of injury?Give examples of the molecules involved.
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
How does binding to a chemotaxin activate neutrophils?
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.
Explain the process of tissue infiltration by neutrophils.
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.
How do neutrophils cross the blood vessel wall into tissues?
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
How do neutrophils recognise bacteria?
1. Via opsonins = plasma proteins that bind the MO to facilitate recogntion. e.g.
- IgG antibody - neutrophil binds Fc
2. In absence of opsonins, neutrophils recognises MO surface antigens
Describe the process of phagocytosis.
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.
What are the 2 main killing mechanisms used by neutrophils?
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')
Why can neutrophils damage host tissues as well as pathogens?
Degranulation begins to occur before the particle is completely enclosed - some toxic metabolites leak out into surrounding tissue spaces.
Name the chemical mediators (and their sources) mediating vasodilation.
1. histamine and serotonin (mast cells, basophils and platelets)
2. prostaglandins (many cells)
Name the chemical mediators (and their sources) mediating increased vascular permeability.
1. histamine and serotonin (mast cells, basophils and platelets)
2. bradykinin (plasma precursor kininogen)
3. leukotrienes (arachidonic acid of leucocytes)
Name the chemical mediators (and their sources) mediating chemotaxis.
1. leukotriene B4 (arachidonic acid of leucocytes)
2. chemokines (leucocytes and other cells)
3. bacterial products
4. C5a and C3a (complement precursors)