Inflammation Flashcards
Describe inflammation.
defense reaction of tissue against damage = remove cause of injury & repair tissue
*innate & adaptive
Describe acute VS chronic inflammation.
acute:
-early stage of infection & prepares for tissue repair
chronic:
-macrophages in injured tissue
Describe the exogenic VS endogenic causes of inflammation.
exogenic:
-physical = mechanical & thermal
-chemical
-biological = bacteria, virus, parasite, fungi
endogenic:
-circulation disorder
-metabolic products
Describe the signs of acute inflammation.
-calor, rubor, tumor, dolor, functio laesa
Describe how the signs of inflammation develop.
-after injury = vasodilation (increase blood flow & rising temp)
-lg volume of blood = hyperaemia (redness) at site
-vascular permeability increase = leak fluids = oedema
-few hrs = leukocytes to endothelium -> extravasation (passing of cells from blood into tissue)
-leukocytes phagocytose pathogens & release mediators
-mediators induce pain
List the mediators of inflammation (7).
- proinflammatory cytokines (TNFa, IL1, IL6, IL8)
- complement components
- prostaglandins
- leukotrienes
- vasoactive amines (histamine, serotonin)
- platelet activating factor (PAF)
- plasma proteases
Describe proinflammatory cytokines.
TNFa, IL1, IL6, IL8
-TNFa & IL1 = fever & stress hormone (NE, vasopressin, activate RAAS)
>induce synthesis of IL6, IL8, & IFNy
-IL6 = release of acute phase proteins ex. c-reactive protein (CRP)
-proinflammatory cytokines activate = cog cascade, release NO, platelet activating factor, prostagladins, & leukotrienes
-IL1, IL6, IL8 = promote chemotaxis, induce extravasation of granulocytes & degranulation of neutrophils
Describe complement components.
-C3a & C5a = increase vascular permeability
-stimulate chemotaxis of neutrophils, eosinophils, & monocytes
Describe prostaglandins.
-contribute to vasodilation, capillary permeability, pain, & fever
-lower BP
-stable prostaglandins (PGE1 & PGE2) = effects of histamine & other inflammatory mediators
-thromboxane A2 = promotes platelet aggregation & vasoconstriction
Describe leukotrienes.
-LTC4, LTD4, LTE4 = slow reacting substances of anaphylaxis (SRS-A) -> induce sm m contraction
-LTB4 = chemoattractant of neutrophils
Describe vasoactive amines.
-histamine & serotonin
-found in platelets, basophils, mast cells
-dilation & increased permeability of capillaries
Describe platelet activating factor (PAF).
-from lipid complex in cell membrane
-induces platelet aggregation
-activates neutrophils & eosinophil chemoattractant
-efflux of plasma proteins -> edema
Describe plasma proteases.
-kinins = bradykinin -> increase capillary permeability & pain
-clotting factors = fibrin peptides
Describe the vascular stage/response of inflammation.
- Phase I = vasoconstriction
- Phase II = active vasodilation
-active hyperemia -> increased cell metabolism -> heat - Phase III = passive vasodilation
-increased vascular permeability -> swelling, pain, impaired function
Describe the cellular stage/response of inflammation sequence of events.
- Chemotaxis = leukocytes migrate
- Rolling = leukocytes express adhesion molecules
- Migration = to tissues
- Phagocytosis = neutrophils & macrophages
Describe leukocyte trafficking.
-first cells to arrive at site = granulocytes (neutrophils), monocytes, NK
-cells held together by cell adhesion molecules (CAM) in order to migrate out of vasculature to tissue or LNs adhere to endothelium
What are the 4 types of CAM?
Selectins, mucins, integrins, Ig-superfamily
Describe selectins.
*bind carbohydrate
1. Selectin L (CD62L) = expressed on leukocytes
2. Selectin P (CD62P) & Selectin E (CD62E) = expressed on endothelium
>P = contained in granules found in endothelial cells & released when granules fuse w/ cell membrane
>E = synthesized de novo
*responsible for leukocyte interaction w/ endothelium
Describe mucins.
-glycosylated, serine & threonine rich proteins that bind to selectins
EX: CD34 or GlyCAM1 on endothelial cells bind to CD62L on leukocytes & PSGL1 on neutrophils binds to selectin E & P on endothelial cells
Describe integrins.
-heterodimeric proteins = a & b chains
>form binding site so Ig superfamily binds
-deficiency in B2 integrins = leukocyte adhesion deficiency (LAD) autosomal recessive -> recurrent bacterial infections
[LAD neutrophils cant extravasate]
Describe CAM of the Ig-superfamily.
-immunoglobulin like domains
-fibronectin domains
-ICAM1 (CD154), ICAM2 (CD102), ICAM3 (CD50), VCAM (CD106)
-Ig superfamily CAMs bind to integrins
-expressed on endothelial cells
-MADCAM1 = Ig like + mucin domains
>migration of leukocytes to mucosa (binds a4b7 (L-PAM) through Ig like domain & CD62L through mucin domain
REMEMBER: L-selectin & Mac 1
Describe leukocyte extravasation.
*endothelial cell activation = cytokines stimulate endothelial cells to increase expression of CAM
1. Rolling = leukocytes bind to selectin E & P
2. Activation = increase chemokine secretion by endothelial cells + chemokine receptor expression on leukocytes
3. Adhesion = integrins on leukocytes bind to endothelium
4. Diapedesis (transendothelial migration) = leukocytes use homotypic binding of platelet endothelial cell adhesion molecule 1 (PECAM1 (CD131) on endothelium self to self binding
[now passed thru into inflamed tissue]
Describe neutrophil extravasation.
-dont bind to endothelial cells
-without inflammation = no expression of selectin E,P & other CAMs
-selectin L & mucin PSG-1 = rolling
-IL8 & MIP1B = activation
-activation = ICAM on endothelium & CD11a/CD18, CD11b/CD18 (LFA1 & MAC1) on neutrophils -> adhesion & diapedesis
-chemokine gradient leads neutrophils to site in the tissue
Describe the extravasation of monocytes.
-VCAM1 & ICAM1 = after the activation stage
-replenish tissue macrophage & DCs
-homeostatic migration regulated by CXCL14
*CD62L = rolling
*MCP1 = activation
*PECAM1 = diapedesis
[complement receptors CR3 & CR4 = bacterial peptides participate in extravasation]
Describe the extravasation of lymphocytes.
-similar to neutrophil extravasation
-inflammatory sites/secondary lymphoid organs
-pass thru high endothelial venules (HEV)
>activation of lymphocytes in HEVs prior to extravasation mediated by = CCL19, CCL21, CXCL12
-selectins E, P, mucins, GLYCAM1, CD34, ICAM1, ICAM2, ICAM3, VCAM1, MADCAM1 = all involved
Describe systemic manifestations of inflammation.
*inflammatory mediators released into circulation = no longer localized
1. Acute phase response
2. Alteration in WBCs (leukocytosis/leukopenia)
3. Fever
4. Sepsis
Describe the acute phase response (APR).
-changes in serum protein (synthesized in liver) = APR
-synthesis via pro inflammatory cytokines by phagocytes (TNFa, IL1, IL6)
-protein conc increase/decrease = acute phase response proteins (APP)
EX: complement system proteins, C reactive proteins (CRP), mannose binding lectin
Describe C reactive proteins. (CRP)
-pentameric proteins
-ligands for CRP = polysaccharides/phosphocholine
-CRP bound to surface -> uptake by phagocytes -> complement attack
Describe other systemic effects of inflammation.
-loss of appetite = anorexia
-altered sleep pattern
-lethargy
-muscular wasting = cachexia
-metabolic acidosis (low blood pH)
Describe inflammation termination mechanisms.
failure to terminate inflammation = chronic inflammation & cell destruction
-short half life of inflammatory mediators
-transforming growth factor beta (TGF) ** from macrophages
-IL4 & IL10 ** = downregulation of TNFa, IL6, IL8
-downreg of pro inflammatory molecules like leukotrienes
-upreg of anti-inflammatory molecules like IL1 receptor antagonist or soluble tumor necrosis factor receptor **
-apoptosis of pro inflammatory cells **
-downreg of receptor activity via high conc of ligands
-granulocytes promote arachidonic acid derived lipoxins **
-resolvins & protectins from omega 3 polyunsat fatty acids = apoptosis of neutrophils
-macrophages leave thru lymphatics
Describe the outcomes of inflammation.
- Resolution = restore inflamed tissue & regen of paraenchymal cell
- Fibrosis = tissue destruction -> collagen scar (pos functional impairment)
- Abscess = pus cavity
- Chronic inflammation = prolonged inflammation due to presence of macrophage -> tissue destruction
