Inflammation and Repair Lecture Notes PDF

Inflammation and Repair PART 2 ACUTE INFLAMMATION VALERIE MATEESCU, M.D. UMKC  Learning Objectives Become familiar with the principal mediators of inflammation: vasoactive amines arachidonic acid metabolites cytokines and chemokines complement system...

Inflammation and Repair PART 2 ACUTE INFLAMMATION VALERIE MATEESCU, M.D. UMKC  Learning Objectives Become familiar with the principal mediators of inflammation: vasoactive amines arachidonic acid metabolites cytokines and chemokines complement system other mediators Recognize the morphologic patterns of acute inflammation: serous inflammation fibrinous inflammation purulent (suppurative) inflammation abscess ulcers Learn the outcomes of acute inflammation: complete resolution healing by connective tissue replacement (scarring, or fibrosis) progression to chronic inflammation Describe systemic changes seen in inflammation Know acute phase reactants and other mediators Mediators of Inflammation Substances that initiate and regulate inflammatory reactions Most important mediators of acute inflammation: ◦ Histamine ◦ Prostaglandins ◦ Leukotrienes ◦ Cytokines (TNF, IL-1, IL-6) (role in fever) ◦ Chemokines ◦ Platelet-activated factor ◦ Complement ◦ Kinins Anti-inflammatory agents that target specific mediators examples: aspirin, acetaminophen Mediators of Inflammation Origin: Produced locally by cells at the site of inflammation (mainly by tissue macrophages, dendritic cells, mast cells): amines, prostaglandins, leukotrienes, cytokines Or derived from circulating inactive precursors (plasma-derived mediators) that are activated at the site of inflammation: complement proteins (produced by liver) Activation: Only when needed, triggered by microbial products and substances released by necrotic cells Most mediators are short-lived: quickly decay or are inactivated by enzymes, or scavenged, or inhibited (system of checks and balances = built-in control mechanisms) One mediator can stimulate the release of other mediators that may amplify or counteract the initial action  Vasoactive Amines: Histamine in mast cells of the connective tissue adjacent to blood vessels in blood basophils and platelets Stored in granules Released by degranulation in response to: Physical injury (trauma, heat, cold) Binding of antibodies to mast cells Products of complement: anaphylatoxins (C3a and C5a) Neuropeptides and cytokines (IL-1, IL-8) Effects: Dilation of arterioles Increase permeability of venules by creating interendothelial gaps in postcapillary venules and binding to H1 receptors on microvascular endothelial cells H1 receptor antagonists drugs: treatment of inflammatory reactions: ◦ allergies Vasoactive Amines: Serotonin (5-hydroxythyptamine) is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells (in gastrointestinal tract=GI) Functions: neurotransmitter in the GI vasoconstrictor Arachidonic Acid Metabolites Lipid mediators prostaglandins and leukotrienes produced from arachidonic acid present in membrane phospholipids Stimulate vascular and cellular reactions in acute inflammation Released from membranes by activated phospholipases (mainly PLA2) Triggers: mechanical, chemical, and physical stimuli Once released from membranes, rapidly converts to bioactive mediators (eicosanoids=20- carbon fatty acids) synthetized by 2 major classes of enzymes: Cyclooxygenases (which generate prostaglandins) Lipoxygenases (which produce leukotrienes and lipoxins) Eicosanoids bind to G-protein-coupled receptors on cells mediating inflammation Principal Actions of Arachidonic Acid Metabolites in Inflammation  Prostaglandins (PGs) Produced by mast cells, macrophages, endothelial cells, and other cells Involved in vascular and systemic reactions of inflammation Generated by the actions of 2 cyclooxygenases (COX-1 and COX-2) COX-2 induced by inflammatory stimuli, generates PGs involved in inflammatory reactions and is low/absent in normal tissues Most important PGs in inflammation: PGE2, PGD2, PGF2a, PGI2 (Prostacyclin), and TXA2 (thromboxane A2) PGD2 (+PGE2) produced by mast cells: vasodilation, increases permeability of postcapillary venules, role in exudation, edema, chemoattractant for neutrophils Platelets: synthesis of TXA2: platelet aggregation and vasoconstrictor → THROMBOSIS Vascular endothelium: formation of prostacyclin (PGI2) and its stable end product PGF1a; vasodilation and inhibitor of platelet aggregation: PREVENTS THROMBOSIS Leukotrienes Produced in leukocytes and mast cells by the action of lipoxygenase Involved in vascular and smooth muscle reactions and leukocyte recruitment LTB4: produced by neutrophils and macrophages: chemotactic agent, activator of neutrophils, aggregation and adhesion, generation of ROSs, release of lysosomal enzymes LTC4 and its metabolites LTD4 and LTE4: produced in mast cells, cause vasoconstriction, bronchospasm (asthma), increase permeability of venules  Lipoxins Generated from AA by the lipoxygenase pathway They suppress inflammation by inhibiting the recruitment of leukocytes Inhibit neutrophil chemotaxis and adhesion to endothelium Neutrophils and platelets needed for their production  Pharmacologic Inhibitors of Prostaglandins and Leukotrienes Cyclooxygenase inhibitors: aspirin and other NSAIDS (eg, ibuprofen) Inhibit both COX-1 and COX-2 and thus block all PGs synthesis (treat pain and fever) Aspirin irreversibly inactivates cyclooxygenase Selective COX-2 inhibitors, newer class, 200-300-fold more potent in blocking COX-2, however may increase the risk of cardiovascular and cerebrovascular events Lipoxygenase inhibitors: Zileuton (tx of asthma) Corticosteroids: broad spectrum anti-inflammatory agents Leukotriene receptor antagonists: Montelukast (tx of asthma) Production of AA metabolites and their roles in Inflammation Zileuton Montelukast Cytokines and Chemokines Proteins secreted by many cell types (activated lymphocytes, macrophages, dendritic cells, endothelial cells, epithelial cells, connective tissue cells) that mediate and regulate immune and inflammatory reactions Tumor necrosis Factor (TNF) and Interleukin-1 (IL-1) ◦ Leukocyte recruitment (by promoting adhesion of leukocytes to endothelium and their migration through vessels) ◦ Produced by macrophages and dendritic cells ◦ TNF also produced by T lymphocytes, mast cells, some epithelial cells ◦ Their secretion stimulated by: microbial products, foreign bodies, necrotic cells ◦ Actions: local and systemic reactions of inflammation Endothelial activation Activation of leukocytes and other cells Systemic acute-phase response: fever, systemic inflammatory response syndrome (SIRS) TNF suppresses appetite → cachexia (weight loss, muscle atrophy, anorexia) seen in cancers ◦ TNF antagonists: tx of chronic inflammatory diseases (RA, psoriasis, some IBDs); complication: ↑ susceptibility to mycobacterial infection  Chemokines Small proteins that act primarily as chemoattractants for specific types of leukocytes Four major groups: ◦ Acting on neutrophils: IL-8→ chemotaxis of neutrophils ◦ Acting on monocytes, eosinophils, basophils, lymphocytes ◦ Acting on lymphocytes ◦ Acting on monocytes and T cells Have 2 main functions: ◦ Acute inflammation ◦ Maintenance of tissue architecture Certain chemokine receptors act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV), the cause of AIDS Not currently chemokine antagonists Other Cytokines in Acute Inflammation IL-6 made by macrophages, involved in local and systemic reactions IL-6 receptor antagonists: tx of RA IL-17 made mainly by T lymphocytes, involved in neutrophil recruitment IL-17 antagonists: tx of psoriasis Type 1 interferons which inhibit viral replication, contribute to some of the systemic manifestations of inflammation Principal Mediators of Inflammation Major roles of cytokines in acute inflammation  Complement System Collection of soluble proteins and their membrane receptors involved in host defense against microbes and in pathologic inflammatory reactions Complement proteins: ◦ more than 20, numbered C1-C9 ◦ During activation, several cleavage products of complement proteins → ↑ vascular permeability, chemotaxis, opsonization ◦ In plasma they are inactive! ◦ By activation become proteolytic enzymes that degrade other complement proteins → enzymatic cascade capable of amplification ◦ Critical step in complement activation: cleavage (proteolysis) of C3 component: Classical pathway: triggered by fixation of C1 to antibody (IgM or IgG combined to antigens) Alternative pathway: triggered by microbial surface molecules (e.g., endotoxins); no antibody Lectin pathway: plasma mannose-binding lectins bind to carbohydrates on microbes and directly activates C1 ❑All 3 pathways → formation of C3 convertase (an enzyme) which splits C3 into 2 functionally distinctive fragments: C3a & C3b Complement System Complement system has 3 main functions: ◦ Inflammation: C5a (+ C4a and C3a) stimulate histamine release from mast cells→↑ vascular permeability and vasodilation (anaphylatoxins) C5a also is a chemotactic agent for neutrophils, monocytes, eosinophils, and basophils ◦ Opsonization and phagocytosis: C3b and its cleavage product inactive C3b when fixed to a microbial cell wall, act as opsonins and → phagocytosis ◦ Cell lysis: Deposition of membrane attack complex (MAC) on cell drills holes in the cell membrane, making the cells permeable to water and ions → their osmotic death (lysis) Important for killing of microbes with thin cell walls (Neisseria species: meningococci and gonococci); these microbes can cause serious disseminated infections in persons with deficiency of the terminal components of complement Complement system Its activation is tightly controlled by cell-associated and circulating regulatory proteins expressed on normal host cells (to prevent healthy tissues from being injured at sites of complement activation) Most important regulatory proteins: C1 inhibitor; its deficiency → hereditary angioedema Decay accelerating factor (DAF) and CD59: two proteins linked to plasma membranes by a glycophophatidyl (GPI) anchor; DAF prevents formation of C3 convertase and CD59 inhibits formation of the MAC; acquired deficiency of GPI anchors → excessive complement activation and lysis of RBCs in paroxysmal nocturnal hemoglobinuria (PNH) Factor H is a plasma protein, cofactor for the proteolysis of the C3 convertase; its deficiency → excessive complement activation; mutations in factor H associated with hemolytic uremic syndrome and wet macular degeneration of the eye  The activation of complement by different pathways leads to cleavage of C3 The functions of the complement system are mediated by breakdown products of C3, other complement proteins, and by the membrane attack complex (MAC) Other Mediators of Inflammation Platelet activating factor (PAF) Products of coagulation Kinins: bradykinin → ↑ vascular permeability and contraction of smooth muscle, dilation of blood vessels, and pain when injected in skin (similar to histamine): mediator in anaphylaxis Neuropeptides Role of Mediators in Different Reactions of Inflammation , IL-6 Morphologic patterns of Acute Inflammation The morphologic hallmarks of acute inflammatory reactions: Dilation of small blood vessels Accumulation of leukocytes and fluid in the extravascular tissue Serous Inflammation Exudation of cell-poor fluid into spaces created by injury to surface epithelia or into body cavities lined by peritoneum, pleura, or pericardium Usually not infected by destructive organisms and does not contain large numbers of leukocytes In body cavities the fluid may be derived from plasma (due to increased vascular permeability) or from secretions of mesothelial cells as a result of local irritation; accumulation of fluid in these cavities is called an effusion Effusions consisting of transudates also occur in noninflammatory conditions: in heart failure, kidney and liver diseases Skin blister resulting from a burn or viral effect (early stage) represents accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin Serous inflammation (advanced stage): cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion Fibrinous Inflammation Develops when the vascular leaks are large or there is a local procoagulant stimulus Higher-molecular-weight proteins such as fibrinogen exit the blood and fibrin is formed and deposited in the extracellular space Fibrinous exudate is characteristic of inflammation in the lining of body cavities (meninges, pericardium, and pleura) Histology: fibrin= eosinophilic (pink) meshwork of threads or amorphous material Conversion of fibrinous exudate to scar tissue within the pericardial sac leads to opaque fibrous thickening of the pericardium and epicardium Fibrinous pericarditis with deposits of fibrin on the pericardium A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P) Purulent Inflammation Production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid Abscesses are localized collections of pus caused by suppuration buried in a tissue, organ, or confined space; produced by seeding of pyogenic bacteria into a tissue  Purulent inflammation with multiple bacterial The abscess contains neutrophils and cellular debris abscesses (arrows) in the lung (Bronchopneumonia) and is surrounded by congested blood vessels Ulcers A local defect, or excavation of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue Cross-section view of a duodenal ulcer crater with an The morphology of a chronic duodenal ulcer acute inflammatory exudate in the base Outcomes of Acute Inflammation Complete resolution Healing by connective tissue replacement (scarring or fibrosis) Progression to chronic inflammation Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation