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THE ACUTE INFLAMMATION AND ACUTE-PHASE RESPONSE Innate immune mechanisms establish a state of inflammation at sites of infection Acute inflammation A rapid response to an injurious agent that serves to deliver leukocytes, plasma proteins and fluids to the site of injury Triggers of acute inflammation • Infections (bacterial, viral, fungal, parasitic) & microbial toxins • Tissue necrosis: ischemia, trauma, physical or chemical injury (e.g., thermal injury; irradiation; some environmental chemicals) • Foreign bodies (splinters, dirt, sutures) • Immune reactions (hypersensitivity or autoimmune reactions) Major components of inflammation – Vascular changes • Vasodilation • Vascular permeability • Increased adhesion of white blood cells – Cellular events • Recruitment and activation of neutrophils (polymorphonuclear leukocytes) and monocytes Classical signs of acute inflammation • • • • • Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of function (functio laesa) Maturation of mononuclear phagocytes and dendritic cells Cellular and Molecular Immunology, 7th ed., 2014 Elservier Macrophages respond to pathogens by using different receptors to stimulate phagocytosis and cytokine secretion Effector functions of macrophages Macrophages respond to infection by secreting inflammatory cytokines Systemic actions of cytokines in inflammation Neutrophils are directed to sites of infection through interactions between adhesion molecules Neutrophil chemotaxis acPGP: N-acetyl Proline-Glycine-Proline – neutrophil chemoattractant MMP: matrix metalloproteinase Neutrophil granulocytes • 68% of circulating leukocytes, 99% of circulating granulocytes • Phagocytic cells • Are not present in healthy tissues • Migration elimination of pathogens (enzymes, reactive oxygen intermediates) • Main participants of acute inflammatory processes Killing of bacteria by neutrophils involves the fusion of two types of granule and lysosomes with the phagosome Killing of bacteria by neutrophils is dependent on a respiratory burst Neutrophils are stored in the bone marrow and move in large numbers to sites of infection, where they act and then die. PUS Pus is a whitish-yellow, yellow, or yellow-brown exudate produced by vertebrates during inflammatory pyogenic bacterial infections. Pus consists of creamy, protein-rich fluid, known as liquor puris, and dead cells. Acute injury of myocardium Fever production in response to TNF, IL-1, and IL-6 proinflammatory cytokines hypothalamic control of body temperature increased ‚set-point’ value fever ACUTE-PHASE REACTION IL-6 Liver ACUTE-PHASE REACTION Pentraxin family: CRP – opsonization, complement activation SAP – opsonization, complement activation, binding of mannose/galactose Collectin family: MBL – part of the complement system (SP-A/D – collectins of lungs) Complement proteins (C1-C9) Fibrinogen blood clotting The kinetics of acute-phase proteins in the blood Chemical mediators Vasodilation – Prostaglandins (PG), nitric oxide (NO) Increased vascular permeability – vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation – C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever • IL-1, IL-6, TNFα, PGE2 Pain • Prostaglandins, bradykinin Tissue damage • Neutrophil and Macrophage products – lysosomal enzymes – Reactive oxygen species (ROS) – NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2 preventing the synthesis of prostaglandins Resolution of acute inflammation Septic shock Triggering factors : • systemic infection (bacteraemia) • microbial cell wall products and/or toxins released from the pathogens into blood circulation. Result: Systemic activation of neutrophils and macrophages High level of cytokine (TNF-alpha) production: „cytokine storm” Excessive inflammatory response Septic shock The key molecule of the process: TNF-alpha TNF-alpha and other inflammatory cytokines capillar permeability blood pressure high fever multiorgan failure DIC disseminated intravascular coagulation Therapy: anti-TNF-alpha antibody DIC Disseminated Intravascular Coagulation • pathologic activation of thrombotic process • distress of thrombotic process, bleeding • other causes: snake bite, septic abortion, acute obstetric complications, malignant tumors, leukemias DIC: Disseminated Intravascular Coagulation