Circulatory changes in inflammation, arachidonic acid-derivatives, cyclooxygenase (COX), edema, lymphatics filiariasis/elephantiasis, pain, phagocytosis, acute phase proteins, fever, inflammation, chronic granulomatous disease, sarcoidosis, wound healing

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

20 September Chemical Mediators of Inflammation: Circulatory changes in inflammation Tissue injury stimulates the release of a number of chemical mediators that promote varied actions Plasma-derived and cell-derived Plasma-derived ones circulate in inactive form and must be activated by activators Cell-derived ones are preformed stored in granules or synthesized de novo on demand Mediators of inflammation are heterogeneous and multifunctional Biogenic amines (histamine), peptides (bradykinin, complement), and archidonic acid-derivatives (prostaglandins) Multifunctional: vasodilation or constriction, activation of inflammatory cells, chemotaxis, cytotoxicity, pain, fever Immediate hypersensitivity The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hr later. The immediate reaction is characterized by vasodilation, congestion, and edema, and the late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells. Normal microcirculation: closed precapillary sphincters Acute inflammation: open precapillary sphincters Chemical Mediators in the Inflammatory Response Chemical Source Major Action Immediate vasodilation and Histamine Mast cell granules increased capillary permeability to form exudate For example, attract Chemotactic factors Mast cell granules neutrophils to site Platelet-activating factor Activate neutrophils (PAF) Cell membranes of platelets Platelet aggregation Cytokines (interleukins, T-lymphocytes, macrophages Increase plasma proteins, ESR lymphokines) Induce fever, chemotaxis, leukocytosis Later response: vasodilation Synthesis from arachidonic Leukotrienes & increased capillary acid in mast cells permeability, chemotaxis Vasodilation, increased Prostaglandins (PGs) Synthesis from arachidonic capillary permeability, pain, acid in mast cells fever, potentiate histamine effect Activation of plasma protein Vasodilation and increased Kinins (e.g., bradykinin) capillary permeability, pain, (kinogen) chemotaxis Vasodilation and increased Activation of plasma protein capillary permeability, Complement system cascade chemotaxis, increased histamine release Arachidonic acid-derivatives are an important group of inflammatory mediators Synthesis of arachidonic acid and its derivatives can be inhibited by several drugs – steroids, NSAIDs (e.g., aspirin), and specific cox-inhibitors. (Action at different levels targeting different enzymes). Phospholipase from leukocytes acts on the phospholipids in cell membranes, forming the arachidonic acid pool As with specific cox-inhibitors and NSAIDs, leukotriene receptor blocking agents can be used to inhibit the inflammatory actions of leukotrienes Arachidonic acid acted on by cyclooxygenase and 5-lipoxygenase COX-1 and COX-2 inhibitors, aspirin, indomethacin inhibit cyclooxygenase Cycloxygenase → prostaglandin G (PGG )2→ prost2glandin H (PGH ) → pro2tacycli2 (PGI 2, PGD , 2GE , t2romboxane A (TXA )2 2 PGI 2 causes vasodilation, inhibits platelet aggregation PGD /P2E – v2sodilation, increased vascular permeability TXA –2causes vasoconstriction, promotes platelet aggregation 5-lipoxygenase → 5-HPETE → 5-HETE, lipoxin A (LXA ) an4 lipox4n B (LXB ) (via 4,2- 4 lipoxygenase) LXA a4d LXB inhi4it neutrophil adhesion and chemotaxis 5-HETE – chemotaxis 5-HPETE → leukotriene A (LTA )4→ leuk4triene C (LTC ) → le4kotrie4e D (LTD ) → 4 4 leukotriene E (4TE ) 4 LTC ,4LTD , 4TE – v4soconstriction, bronchospasm, increased vascular permeability Cyclooxygenase (COX) exists in two isoforms: COX-1, which is expressed in most tissues and COX-2, which is induced at sites of inflammation Most NSAIDs work by indiscriminately inhibiting both cyclooxygenase isoforms and thus exhibit analgesic, antipyretic, anti-inflammatory, and antiplatelet effects Indiscriminate COX inhibition has several risks Gastric bleeding Premature closure of ductus arteriosus Reye’s syndrome – potentially lethal condition in children that results in hepatotoxicity and/or encephalopathy due to use of aspirin during a viral illness; may be due to shunting of arachidonic acid to leukotrienes and lipoxin metabolites To bypass the risk of gastric bleeding associated with COX inhibition, COX-2-specific inhibitors were developed At least one COX-2 inhibitor was withdrawn because of cardiovascular risk (mortality) Prostaglandins keep fetal shunts functional NSAIDs inhibit prostaglandin synthesis and may act as endocrine disruptors Physiologic stimulus → COX-1, constitutive (stomach, kidney, intestine, platelets, endothelium) → PGE , TXA 2 PGI →2physio2ogic functions Inflammatory stimulus → COX-2, inducible (inflammatory sites [macrophages, ·- synovicocytes]) → inflammatory VGs, proteases, O → inflamma2ion Both pathways inhibited by NSAIDs Pathogenesis of Edema Important pathogenic factors Increased venous pressure Reduced oncotic pressure of plasma resulting from low albumin concentration Increased permeability of the vessel wall Obstruction of lymphatics Venous thrombosis, heart failure → increased hydrostatic pressure Nephrotic syndrome, enteropathy, liver failure → decreased oncotic pressure Inflammation, trauma, burns → increased vascular permeability Parasites, tumors, surgery → obstruction of lymph flow Lymphatics Filariasis/Elephantiasis Helminths (worms) are among the most common human pathogens. From 25% to 50% of the world’s population is infected with one or more species of worm. About 100 to 200 million people are infected with one of two species of filarial (thread-like) roundworms. The infection is spread by bites from several different species of mosquito that carry infectious worm larvae. Hundreds of bites, presumably to build up the parasitic load, are usually required for infection. The larvae migrate to the lymphatic vessels and lymph nodes, where they mature into adult worms. They accumulate in regions with large numbers of lymph nodes. After male and female worms mate, the female releases microfilariae into the lymphatics and bloodstream. The pathologic and physiologic consequences are the result of the immune response to degenerating adult worms. These responses include activation of TH2 lymphocytes and accumulation of lymphocytes, eosinophils, macrophages, and plasma cells. The infections persist for years, and many asymptomatic individuals have near-total blockage of the lymphatics of the arms, legs, or testes. Such individuals have massive lymphedema, called elephantiasis, of the limbs or scrotum. Engorgement of the scrotum (hydrocele) is about 10 times as common as that of the limbs. Male hydrocele can be alleviated by a simple surgical procedure, but this is generally unavailable in affected parts of the world. Infection with filial worms can be prevented by the addition of one of several drugs to table salt. Pain Psychogenic pain Organic pain Neuropathic pain CNS injury Peripheral ner
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