Inflammation I Flashcards
Acute inflammation
Minutes - hours
Mainly neutrophils
Usually mild and self limiting
Prominent local and systemic signs
Chronic inflammation
Days
Monocytes/macrophages and lymphocytes
Often severe and progressive tissue injury and fibrosis
Less local and systemic signs
Causes of acute inflammation
Infections
Tissue necrosis from ischemia, trauma, and physical/chemical injury
Foreign bodies
Immune or hypersensitivity rxns
Mechanism of microbe recognition
Cellular receptor for microbes (TLRs)
Cytosol receptors that recognize molecules released with cell damage
Other cellular receptors involved in inflammation
Circulating proteins (complement system)
Signs of inflammation
Redness
Swelling
Heat
Pain
Vascular changes in acute inflammation
Vasodilation (heat and redness)
Increased permeability of microvasculature, causing edema, an excess of interstitial fluid or cavity fluid
Stasis of blood flow (vascular congestion)
Neutrophils marinate, adhere to endothelium and then migrate through vessel into interstitium
Exudate
Fluid high in protein and cellular content
Pus: purulent exudate rich in wbc, necrotic debris, and sometimes microbes
Transudate
Fluid low in protein and cellular content
Associated with low serum albumin or increase hydrostatic pressure (such as heart failure)
Cellular events in acute inflammation
Extravasation: journey of leukocyte from vessel lumen to interstitial tissue
Steps involved:
1. Adhesion of leukocyte to vascular endothelium
2. Transmigration across endothelium (diapedesis)
3. Chemotaxis
4. Leukocyte activation
5. Phagocytosis
Inflammatory mediators
Redistribution of adhesion molecule P-selectin (redistribution induced by histamine and thrombin and activated by cytokines, histamine, or thrombin)
Induction of adhesion molecule synthesis of E-selectin and ligand for integrins (VCAM1, ICAM1) in endothelial cells in 2-3hrs (induced by IL1 and TNF)
Increase in binding affinity of leukocyte integrins induced by chemokines
Transmigration/Diapedesis
Migration of leukocytes through endothelium
After transverse game endothelium, leukocytes pierce basement membrane (probably secrete collagenases and enter extravascular tissue)
Neutrophils predominate cells that transmigrate during acute inflammation
Chemotaxis
Exogenous: originating from source of inflammation
Bacterial products
Endogenous: produced by injured host
Complement components (C5a), leukotriene B4 (LTB4), and chemokines (IL8)
Chemoattractants induce leukocyte movement -> binds receptor -> activates phospholipase C -> inc intracellular Ca -> triggers cross linking of actin -> pseudopod
Activation of leukocytes
- Recognition of offending agents which signals
2. Activate leukocytes to ingest and destroy offending agents and amplify inflammatory reaction
Response to leukocyte activation
- Amplification of inflammatory reaction
Produce arachidonic acid metabolites by leukocyte
Secretion of cytokines by leukocyte - Degranulation and release of lysosomal enzymes
- Phagocytosis and activation of oxidative burst within leukocyte
- Increase in binding affinity of adhesion molecules
- Chemotaxis
Nitric oxide
Soluble gas produced by endothelial cells and macrophages
Vasodilator
Kills microorganisms
Neutrophil extracellular traps (NETS)
Fibrillary networks containing antimicrobial substances produced by neutrophils
Microbes caught in fibrils
Consists of:
1. Nuclear chromatin (neutrophil extrudes it nucleus killing the cell)
2. Contents of cytoplasmic granules which contain antimicrobial proteins and enzymes
Major inflammatory mediators
Vasoactive amines
Lipid products (prostaglandins and leukotrienes)
Cytokines, including chemokines
Complement
One mediator can stimulate release of other mediators
Vasoactive amines
Histamine: mast cells, basophils, platelets
Dilation of arterioles and increase permeability of venules by producing interendothelial gaps due to contraction of endothelial cells
Induce synthesis of prostacyclin and nitric oxide
Serotonin: platelets and some neuroendocrine cells
Released with histamine during platelet aggregation
Vasoconstrictor
Neurotransmitter in GI tract
Arachidonic acid metabolites
Concerted by enzymes into prostaglandins and leukotrienes when cells are activated by diverse stimuli
Cyclooxygenase pathway products
PGI2 (prostacyclin): vasodilation and inhibits platelet aggregation
Thromboxane A2: vasoconstriction and promotes platelet aggregation
PGD2, PGE2, and PGF2: vasodilation, potentiate edema by enhancing vascular permeability effects of other mediators (PGE2 pain and involved in cytokine, induced fever with infections)
Lipoxygenase pathway products
Leukotrienes B4: neutrophil chemotaxis
Leukotriene C4, D4, and E4: increase vascular permeability by endothelial cell contraction, vasoconstriction, bronchospasm
Lipoxins A4 and B4: INHIBITOR of inflammation
Cytokines and chemokines
Cytokines: mediate and regulate immune and inflammatory rxns
IL1 and TNF
Chemokines: small proteins acting as chemoattractants
Complement system
Enzymatic cascade C5b-C9: membrane attack complex C3a, C5a: anaphylatoxins, stimulate release of histamine C5a: leukocyte chemotactic factor C3b: opsonin
Regulatory proteins of complement
C1 inhibitor: block activation of C1
Decay accelerating factor (DAF): prevents formation of C3 convertase
CD59: inhibits formation of membrane attack complex
Platelet Activating Factor
Causes platelet aggregation
Vasoconstriction and bronchoconstriction
Increased leukocyte adhesion to endothelium, chemotaxis, degranulation, and oxidative burst
Boosts synthesis of other mediators, especially eicosanoids
Kinin system
Vasoactive peptides
Kallikrein cleaves kininogen into bradykinin
Bradykinin: vasodilation and increased vascular permeability, major contributor to pain, bronchoconstriction
