Chemical Mediators in Inflammation PDF

CHEMICAL MEDIATORS IN INFLAMMATION Bassmah Alblaihed PATHOLOGY 6  Objectives of the lecture Upon completion of this lecture, students should be able to: § Have some understanding of the various chemical mediators of inflammation and their link with t...

CHEMICAL MEDIATORS IN INFLAMMATION Bassmah Alblaihed PATHOLOGY 6  Objectives of the lecture Upon completion of this lecture, students should be able to: § Have some understanding of the various chemical mediators of inflammation and their link with the complement system and potentially with coagulation factors § Recognize the different morphologic patterns of acute inflammation Overview Chemical mediators of inflammation: 1. Substances produced during inflammation, inducing specific events in inflammation 2. Responsible for the vascular and cellular events in acute inflammation 3. Initiate and regulate inflammatory reactions Source of Chemical mediators Plasma-derived Cell-derived Complement Preformed, sequestered and kinins released (mast cell histamine) Coagulation factors Synthesized as needed (prostaglandin) Many in “pro-form” requiring activation (enzymatic cleavage)  Cell derived Histamine Mast cells are the major sources of it (basophils and platelets) Histamine causes dilation of arterioles and increases the vascular permeability. Histamine is released from mast cell in response to: § Immune reactions § Physical injury (trauma or heat) § IL-1 and IL-8 § C3a and C5a § Leukocyte-derived histamine-releasing proteins  Cell derived Arachidonic Acid (AA) Metabolites AA is fatty acid present in the body as a component of cell membrane phospholipids. It is released from these phospholipids via cellular phospholipases that have been activated by: § Mechanical stimuli § Chemical stimuli § Physical stimuli § Inflammatory mediators such as C5a AA mediators are synthesized by two major classes of enzymes: § Cyclooxygenase (prostaglandins) § Lipoxygenase (leukotrienes and lipoxins)  Cell derived Prostaglandins Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells Prostaglandins are involved in the vascular and systemic reactions of inflammation: § PGD2 & PGE2 cause vasodilation and increases the permeability of venules § PGI2 is a vasodilator § Prostaglandins are involved in the pathogenesis of pain and fever (PGE2) Cell derived Leukotrienes Leukotrienes are produced in leukocytes and mast cells. Leukotrienes are involved in vascular reactions and leukocyte recruitment: § LTB4 is a potent chemotactic agent and activator of neutrophils. § LTC4 , LTD4 ,LTE4, cause increased permeability of venules  Cell derived Lipoxins Lipoxins also are generated from arachidonic acid by the lipoxygenase pathway. Leukocytes (neutrophils) produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets. The lipoxins inhibit neutrophil chemotaxis and adhesion to endothelium. Principal Actions of (AA) Metabolites in Inflammation Arachidonic Acid (AA) Action Metabolites Vasodilation PGI2 (prostacyclin), PGE2, PGD2 Increased vascular permeability Leukotrienes C4, D4, E4 Chemotaxis Leukotriene B4  Cell derived Cytokines and Chemokines Cytokines are proteins secreted by many cell types that mediate and regulate immune and inflammatory reactions. Tumor Necrosis Factor (TNF) & Interleukin-1 (IL-1) Macrophages and dendritic cells produce TNF and IL-1 The secretion of TNF and IL-1 can be stimulated by: § Microbial products § Foreign bodies § Necrotic cells § Immune complexes Tumor Necrosis Factor (TNF) & Interleukin-1 (IL-1) (contd) TNF and IL-1 serve critical roles in leukocyte recruitment by promoting: § Adhesion of leukocytes to endothelium § Their migration through vessels TNF stimulates the microbicidal activity of macrophages. IL-1 activates fibroblasts to synthesize collagen. IL-1 and TNF induce systemic acute-phase response.  Cytokines and Chemokines (contd) Chemokines are a family of small proteins that act as chemoattractants for specific types of leukocytes. Chemokines recruit leukocytes during inflammatory responses Chemokines are produced by a variety of cell types and differ widely in biological action. Inflammatory chemokines are elicited by: § Bacterial toxins § Inflammatory cytokines (IL-1, TNF-α, IFN-γ)  Plasma derived Complement System § The complement system is a group of proteins found in plasma and on cell surfaces. § The complement system has over 30 proteins, including plasma enzymes, regulatory proteins and cell lysis proteins. § They are mainly made in the liver and are activated in sequence. § Complement system main function is defense against microbes. Complement System (contd) The complement component functions in inflammation: § Increase vascular permeability and vasodilation. § Activated complement proteins act as opsonins § Potent chemotactic agent for leukocytes § Activates AA metabolism pathway. § Activates leukocytes. § Cell lysis  Plasma derived Products of Coagulation Factor XIIa initiates four systems involved in inflammation: § The kinin system § The clotting system § The fibrinolytic system § The complement system Factor Xa causes increased vascular permeability and leukocyte emigration. Thrombin enhanced leukocyte adhesion Fibrin degradation products increase vascular permeability.  Plasma derived Kinin system § The kinin system is initiated by activated Hageman factor (factor XIIa) § Plasma kallikrein is generated by activated factor XII (Conversion of prekallikrein to kallikrein) § kallikrein is a chemotactic factor. § Activitiation of kinin system results in the cleavage of kininogen to bradykinin by kallikrein § Bradykinin mediates vascular permeability, arteriolar dilation, and pain. Role of Mediators in Different Reactions of Inflammation Vasodilation § Prostaglandins § Histamine Increased vascular § Histamine permeability § Bradykinin § Leukotrienes C4, D4, E4 Leukocyte recruitment § Chemokines and activation § Leukotriene B4 Fever § IL-1, TNF § Prostaglandins Pain § Prostaglandins § Bradykinin Tissue damage § Lysosomal enzymes of leukocytes § Reactive oxygen species § Nitric oxide  Morphologic Patterns of Acute Inflammation § Serous Inflammation § Fibrinous Inflammation § Suppurative Or Purulent Inflammation § Ulcers Serous inflammation It is characterized by the accumulation of a watery, relatively protein-poor fluid. This fluid derives either from the serum or from the secretions of mesothelial cells lining the serous cavities The skin blister resulting from a burn or viral infection is an example of a serous inflammation.  Fibrinous inflammation It results from severe injuries, causing greater vascular permeability that allows large molecules (fibrinogen) to pass the endothelial barrier (fibrinous exudate) This fibrinous exudate is characteristic of inflammation in the lining of body cavities. Such exudates may be degraded by fibrinolysis, and the accumulated debris may be removed by macrophages. Failure to completely remove this exudate results in scarring that may have significant clinical outcomes.  Suppurative Or Purulent Inflammation Abscess § This is a cavity filled with pus. § The cavity is surrounded by fibrous tissue. § It results from tissue destruction by lysosomal products and other enzymes. § It is usually caused by bacterial infections (staphylococci) Purulent exudate (pus) associated with suppurative inflammation consisting of: § Neutrophils § Necrotic cells § Edema fluid Ulcer § An ulcer, a defect in the surface lining of the skin or mucosae, results from inflammation induced necrosis of the superficial layers of the involved organ § Ulceration can occur only when tissue inflammation and necrosis is present on or near a surface Fistula § A tract (a passage) between two surfaces