Acute and Chronic Inflammation.pdf

Acute and Chronic Inflammation Karen Gil MD. MSHN Inflammation • Protective response intended to eliminate the initial cause of cell injury and its consequences as necrotic cells and tissues • Essential for repair Destroys, wall off or dilute the injurious agent and sets in motion tissue healing (...

Acute and Chronic Inflammation Karen Gil MD. MSHN Inflammation • Protective response intended to eliminate the initial cause of cell injury and its consequences as necrotic cells and tissues • Essential for repair Destroys, wall off or dilute the injurious agent and sets in motion tissue healing (fibrous scar tissue) Components of acute and chronic inflammatory response • Circulating cells and proteins • Vascular wall cells • Connective tissue cells Acute Inflammation 1. Acute inflammation start when immune cells as macrophages respond to an inflammatory stimuli – Pathogen: bacteria, virus, protozoan – Injury – Toxins 2. Immune cell receptor triggers a signal cascade, activating production of – Cytokines – Inflammatory mediators Acute Inflammation • Acute inflammation is an immediate and early response to injury • Short duration • Two major stages – Vascular stage • Vasodilatation • Increased vascular permeability – permit plasma proteins to leave the circulation – Cellular stage • Cellular recruitment and activation – Emigration of leukocytes from the microcirculation – Accumulation in the focus of injury • Phagocytosis stage Signs of Inflammation • Heat (calor) • Redness (rubor) • Pain (dolor) • Swelling (tumor) • Loss of function (functio laesa) Vascular Changes 1. Vasoconstriction – immediate-transient response 2. Arteriolar Vasodilatation – Increased blood flow – Engorgement of the downstream capillary beds • clinically evidenced as heat and erythema (redness) Increased vascular permeability • Earliest phase of inflammation– arteriolar vasodilatation and augmented blood flow increase intravascular hydrostatic pressure and the movement of fluid from capillaries • Transudate – Fluid accumulated in third spaces with low protein concentration • Exudate – Fluid accumulated in third spaces with high Protein concentration Acute Inflammation Vascular Stage Vasoconstriction Immediate Vasodilation induced by chemicals inflammatory increasing blood flow enhancing his permeability allows plasma and immune cells to enter to the inflamed tissue Clinical signs: redness, heat and swelling Acute Inflammation Cellular Stage • Sequence of extravasation of leukocytes from vascular lumen to extravascular space – Migration – Rolling – Adhesion – Transmigration CELLULAR Delivery and activation of Leukocytes division steps Margination Rolling Adhesion EVENTS Transmigration Cellular Stage • Leukocyte influx – Primarily neutrophils into the injury site (function- host defense) – Slow blood flow allowing leukocyte adhere to the blood vessel wall – Then transmigrate from vascular space to the extracellular space – After extravasation, leukocytes migrate into the tissue injury by chemotaxis Cellular Response • Chemotaxis – Leukocytes migrate toward sites of injury along a chemical gradient • Activation – Degranulation and secretion of lysosomal enzymes (activation of protein kinase C) – Production of AA metabolites (activation of phospholipase A2) PHAGOCYTOSIS 3rd stage • Opsonins enhance recognition and phagocytosis of bacteria • Tree steps Opsonization: 1. Receptor activation by complement factor C3b and antibody facilitates recognition by neutrophil 2. Phagosome enclose the microbe 3. Phagolysosome - lysosomal enzymes and oxygen radicals are released to kill and degrade the microbe Defects in leukocyte function • Defects in adhesion – Cell adhesion molecules (easy acquire infections, and fever) • Defects in chemotaxis and phagocytosis – Chédiac-Higashi syndrome • Abnormal lysosomes, bacteria can’t be lysed normally • AR disorder (busing, oculocutaneous albinism, recurrent pyogenic infections) • Defects in bactericidal activity – Chronic granulomatous diseases • Mixed defects Leukocyte induced injury or function defect Clinical Examples of Leukocyte-Induced Injury Acute Chronic Acute respiratory distress syndrome Arthritis Acute transplant rejection Asthma Asthma Atherosclerosis Glomerulonephritis Chronic lung disease Reperfusion injury Chronic rejection Septic shock Vasculitis Chemical mediators of inflammation Vasoactive Amines Histamine, Serotonin and Bradykinin HISTAMINE •Produced by basophils, platelets and mast cells •Effect: vasodilatation and increased vascular permeability •Triggers for release: 1- Physical trauma 2- Immune reactions involving IgE ab against Fc receptors of Mast cells 3- C3a and C5a fragments (anaphylatoxins) 4- Leukocyte derived histamine- release proteins 5- Neuropeptides (Substance P) 6- Cytokines (Il-1) Vasoactive Amines Serotonin • Produced by platelets • Effect: vasodilatation and increased vascular permeability Bradykinin • Released in the kinin cascade (vasoactive kinins) • Effects: increased vascular permeability, pain, vasodilatation, bronchoconstriction Plasma Proteases • Many effects of inflammation are mediated by three inter-related plasma derived factors: Linked by the initial activation Clotting cascade of Complement cascade Haggeman Factor Kinin system (F XII) of the intrinsic coagulation cascade Coagulation cascade Eicosanoids Arachidonic Acid metabolites that can mediate virtually every step of inflammation • Leukotrienes • Prostaglandins – – Prostacylin Tromoboxane A2 • Lipoxins Inflammatory Actions of Eicosanoids Action Metabolite Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4 Vasodilation PGI2, PGE1, PGE2, PGD2 Increased vascular permeability Leukotrienes C4, D4, E4 Chemotaxis, leukocyte adhesion Leukotriene B4, HPETE, lipoxins Cytokines activate inflammatory cells during cell mediated responses as interleukin (IL-1) and tumor necrosis factor (TNF) Outcomes of Acute Inflammation 1- Complete resolution ( short lived process with regeneration) 2- Scarring or fibrosis (occurs in tissues that lack regeneration or after extensive tissue destruction) 3- Abscess formation (certain microbial infections) 4- Progression to Chronic inflammation Events in complete resolution of inflammation 1. Return to normal vascular permeability 2. Removal of edema fluid and proteins by drainage into lymphatics 3. Macrophage pinocytosis 4. Phagocytosis of apoptotic neutrophils 5. Necrotic debris by macrophages 6. Eventual exodus of macrophages Chronic Inflammation Characterized by: 1- Infiltration of mononuclear cells Macrophages Lymphocytes Plasma cells 2- Tissue destruction 3- Repair by angiogenesis (vessel proliferation) and fibrosis • Chronic inflammation may be considered a persistent process of long duration (weeks to months) • Etiologies: – May follow acute inflammation – Viral infections – Persistent infection (Mycobacterium sp. Treponema pallidum, etc.) – Prolonged exposure to toxic agents – Autoimmune disease Important cells in chronic inflammation • Macrophages – – – – – arise from blood monocytes have a life span of several months phagocytic cell may be activated secrete a variety of biologically active mediators of tissue destruction and fibrosis ▪ ▪ ▪ ▪ ▪ ▪ Enzymes Plasma proteins Reactive metabolites of Oxygen Lipid mediators or eicosanoids (AA) Cytokines (IL-1 and TNF) Growth factors Products made by activated macrophages Fibrosis • Proliferation of fibroblasts • Common feature of many chronic inflammatory diseases and an important loss of organ function Granuloma • Specialized form of chronic inflammation characterized by ▪ Microscopic aggregation of transformed macrophages (epithelioid cells) surrounded by a collar of mononuclear cells (lymphocytes and plasma cells) • Types: ▪ Non-caseous ▪ Caseous Granuloma Granulomatous inflammation Distinctive pattern common to few diseases Diseases with Granulomatous Inflammations Disease Cause Tissue Reaction Tuberculosis Mycobacterium tuberculosis Caseating tubercle (granuloma prototype): a focus of epithelioid cells, rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cell; caseating tubercle: central amorphous granular debris, loss of all cellular detail; acid-fast bacilli Leprosy Mycobacterium leprae Acid-fast bacilli in macrophages; non-caseating granulomas Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic without loss of cellular outline Cat-scratch disease Gram-negative bacillus Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon Morphologic patterns in acute and chronic inflammation • Serous inflammation • Fibrinous inflammation • Suppurative inflammation • Ulcer Serous inflammation • Characterized by outpouring of watery protein-poor fluid (effusion) • Fluid may arise from serum or from mesothelial cells • Example: blister Fibrinous inflammation •Severe injuries •Characterized by fibrinous exudates •Can develop to a scar or restoration of the tissue Suppurative inflammation •Characterized for large amounts of purulent exudates (pus) •Pyogenic organisms (e.g. staphyloccoci) •Central necrotic region rimmed by a layer of neutrophils •Eventually replaced by connective tissue Ulcer •Epithelial surface has become necrotic •Secondary to toxic or traumatic injury to the epithelial surface •The surrounding area develops fibroblastic proliferation, scarring and accumulation of chronic inflammatory cells Systemic Manifestations of Inflammation • • • • Fever Somnolence Myalgias Anorexia (general malaise) • Leukocytosis (15,000 – 20,000 cells/ ul) Features of Acute and Chronic Inflammation Feature Onset Acute Fast: minutes or hours Cellular infiltrate Mainly neutrophils Tissue injury, fibrosis Usually mild and self-limited Often severe and progressive Local and systemic signs Prominent Chronic Slow: days Monocytes/macrophages and lymphocytes Less prominent; may be subtle https://www.youtube.com/watch?v=uc6IV85mf3s Drug Therapy • Aspirin and NSAIDs – block the synthesis of prostaglandin in PNS • Corticosteroids – inhibition of interleukin-1, cytokines, and TNFs – also impair phagocytosis by preventing phagocytic cells from leaving the bloodstream – They decrease the number of lymphocytes, fibroblasts, and collagen needed for tissue repair