Inflammation (Acute & Chronic) PDF

INFLAMMATION (ACUTE & CHRONIC) Introduction Injurious stimuli cause a protective vascular connective tissue reaction called “inflammation” o Dilute o Destroy o Isolate o Initiate repair...

INFLAMMATION (ACUTE & CHRONIC) Introduction Injurious stimuli cause a protective vascular connective tissue reaction called “inflammation” o Dilute o Destroy o Isolate o Initiate repair Acute and chronic forms Acute inflammation Immediate and early response to tissue injury (physical, chemical, microbiologic, ) o Vasodilation o Vascular leakage and edema o Leukocyte emigration (mostly PMNs, i.e, Neutrophils) Vasodilation Brief arteriolar vasoconstriction followed by vasodilation o Accounts for warmth and redness o Opens microvascular beds o Increased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into interstitium (vascular permeability still not increased yet) Vascular leakage Vascular permeability (leakiness) commences o Transudate gives way to exudate (protein-rich) o Increases interstitial osmotic pressure contributing to edema (water and ions) Five mechanisms known to cause vascular leakiness o Histamines, bradykinins, leukotrienes cause an early, brief (15 – 30 min.) immediate transient response in the form of endothelial cell contraction that widens intercellular gaps of venules (not arterioles, capillaries) o Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction through cytoskeleton reorganization (4 – 6 hrs post injury, lasting 24 hrs or more) o Severe injuries may cause immediate direct endothelial cell damage (necrosis, detachment) making them leaky until they are repaired (immediate sustained response), or may cause delayed damage as in thermal or UV injury,  o (cont’d) or some bacterial toxins (delayed prolonged leakage) o Marginating and endothelial cell-adherent leukocytes may pile-up and damage the endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent endothelial cell injury) making the vessel leaky o Certain mediators (VEGF) may cause increased transcytosis via intracellular vesicles which travel from the luminal to basement membrane surface of the endothelial cell All or any combination of these events may occur in response to a given stimulus Leukocyte cellular events Leukocytes leave the vasculature routinely through the following sequence of events: o Margination and rolling o Adhesion and transmigration o Chemotaxis and activation They are then free to participate in: o Phagocytosis and degranulation o Leukocyte-induced tissue injury Margination and Rolling With increased vascular permeability, fluid leaves the vessel causing leukocytes to settle-out of the central flow column and “marginate” along the endothelial surface Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium like a tumbleweed until it eventually comes to a stop as mutual adhesion reaches a peak Early rolling adhesion mediated by selectin family: o E-selectin (endothelium), P-selectin (platelets, endothelium), L-selectin (leukocytes) bind other surface molecules (i.e.,CD34, Sialyl-Lewis X-modified GP) that are upregulated on endothelium by cytokines (TNF, IL-1) at injury sites Adhesion Rolling comes to a stop and adhesion results Other sets of adhesion molecules participate: o Endothelial: ICAM-1, VCAM-1 o Leukocyte: LFA-1, Mac-1, VLA-4 (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4) Ordinarily down-regulated or in an inactive conformation, but inflammation alters this Transmigration (diapedesis) Occurs after firm adhesion within the systemic venules and pulmonary capillaries via PECAM –1 (CD31) Must then cross basement membrane o Collagenases o Integrins Early in inflammatory response mostly PMNs, but as cytokine and chemotactic signals change with progression of inflammatory response, alteration of endothelial cell adhesion molecule expression activates other populations of leukocytes to adhere (monocytes, lymphocytes, etc) Chemotaxis Leukocytes follow chemical gradient to site of injury (chemotaxis) o Soluble bacterial products o Complement components (C5a) o Cytokines (chemokine family g., IL-8) o LTB4 (AA metabolite) Chemotactic agents bind surface receptors inducing calcium mobilization and assembly of cytoskeletal contractile elements Chemotaxis and Activation Leukocytes: o extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxis o undergo activation: ▪ Prepare AA metabolites from phospholipids ▪ Prepare for degranulation and release of lysosomal enzymes (oxidative burst) ▪ Regulate leukocyte adhesion molecule affinity as needed Phagocytosis and Degranulation Once at site of injury, leukocytes: o Recognize and attach o Engulf (form phagocytic vacuole) o Kill (degrade) Recognition and Binding Opsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG) Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding Oxidative burst Reactive oxygen species formed through oxidative burst that includes: o Increased oxygen consumption o Glycogenolysis o Increased glucose oxidation o Formation of superoxide ion ▪ 2O2 + NADPH ® 2O2-rad + NADP+ + H+ (NADPH oxidase) ▪ O2 + 2H+ ® H2O2 (dismutase) Reactive oxygen species Hydrogen peroxide alone insufficient MPO (azurophilic granules) converts hydrogen peroxide to HOCl- (in presence of Cl- ), an oxidant/antimicrobial agent Therefore, PMNs can kill by halogenation, or lipid/protein peroxidation Degradation and Clean-up Reactive end-products only active within phagolysosome Hydrogen peroxide broken down to water and oxygen by catalase Dead microorganisms degraded by lysosomal acid hydrolases Leukocyte granules Other antimicrobials in leukocyte granules: o Bactericidal permeability increasing protein (BPI) o Lysozyme o Lactoferrin o Defensins (punch holes in membranes) Mediators causing Inflammation 1. Chemical mediators Plasma-derived: o Complement, kinins, coagulation factors o Many in “pro-form” requiring activation (enzymatic cleavage) Cell-derived: o Preformed, sequestered and released (mast cell histamine) o Synthesized as needed (prostaglandin) May or may not utilize a specific cell surface receptor for activity May also signal target cells to release other effector molecules that either amplify or inhibit initial response (regulation) Are tightly regulated: o Quickly decay (AA metabolites), are inactivated enzymatically (kininase), or are scavenged (antioxidants) 2. Specific mediators Serotonin: vasodilatory effects similar to those of histamine; platelet dense-body granules; release triggered by platelet aggregation  Plasma proteases o Clotting system o Complement o Kinins (i.e. bradykinin) Kinin system Leads to formation of bradykinin from cleavage of precursor (HMWK) o Vascular permeability o Arteriolar dilation o Non-vascular smooth muscle contraction (e.g., bronchial smooth muscle) o Causes pain o Rapidly inactivated (kininases) Complement system Components C1-C9 present in inactive form o Activated via classic (C1) or alternative (C3) pathways to generate MAC (C5 – C9) that punch holes in microbe membranes o In acute inflammation ▪ Vasodilation, vascular permeability, mast cell degranulation (C3a, C5a) ▪ Leukocyte chemotaxin, increases integrin avidity (C5a) ▪ As an opsonin, increases phagocytosis (C3b, C3bi) Leukotrienes: via lipoxygenase pathway; are chemotaxins, vasoconstrictors, cause increased vascular permeability, and bronchospasm PAF (platelet activating factor) o Derived also from cell membrane phospholipid, causes vasodilation, increased vascular permeability, increases leukocyte adhesion (integrin conformation) More specific mediators Cytokines o Protein cell products that act as a message to other cells, telling them how to behave. o IL-1, TNF-a and -b, IFN-g are especially important in inflammation. o Increase endothelial cell adhesion molecule expression, activation and aggregation of PMNs, etc., etc., etc. Possible outcomes of acute inflammation Complete resolution o Little tissue damage o Capable of regeneration Scarring (fibrosis) o In tissues unable to regenerate o Excessive fibrin deposition organized into fibrous tissue Abscess formation occurs with some bacterial or fungal infections Progression to chronic inflammation (next) Chronic inflammation Lymphocyte, macrophage, plasma cell (mononuclear cell) infiltration Tissue destruction by inflammatory cells Attempts at repair with fibrosis and angiogenesis (new vessel formation) When acute phase cannot be resolved o Persistent injury or infection (ulcer, TB) o Prolonged toxic agent exposure (silica) o Autoimmune disease states (RA, SLE) The Players (mononuclear phagocyte system) Macrophages o Scattered all over (microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc. o Circulate as monocytes and reach site of injury within 24 – 48 hrs and transform o Become activated by T cell-derived cytokines, endotoxins, and other products of inflammation T and B lymphocytes o Antigen-activated (via macrophages and dendritic cells) o Release macrophage-activating cytokines (in turn, macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed) Plasma cells o Terminally differentiated B cells o Produce antibodies Eosinophils o Found especially at sites of parasitic infection, or at allergic (IgE-mediated) sites Patterns of acute and chronic inflammation Serous o Watery, protein-poor effusion (e.g., blister) Fibrinous o Fibrin accumulation o Either entirely removed or becomes fibrotic Suppurative o Presence of pus (pyogenic staph spp.) o Often walled-off if persistent Ulceration o Necrotic and eroded epithelial surface o Underlying acute and chronic inflammation o Trauma, toxins, vascular insufficiency Systemic effects Fever o One of the easily recognized cytokine-mediated (esp. IL-1, IL-6, TNF) acute-phase reactions including ▪ Anorexia ▪ Skeletal muscle protein degradation ▪ Hypotension o Leukocytosis ▪ Elevated white blood cell count ▪ Bacterial infection (neutrophilia) ▪ Parasitic infection (eosinophilia) ▪ Viral infection (lymphocytosis)