Acute and Chronic Inflammation PDF

# **Inflammation** ## **Introduction** - Inflammation is a protective response of living vascularized tissue to injury of any cause - The primary function of the inflammatory response is to eliminate a pathogenic insult and remove injured tissue components, thus allowing tissue repair to take plac...

# **Inflammation** ## **Introduction** - Inflammation is a protective response of living vascularized tissue to injury of any cause - The primary function of the inflammatory response is to eliminate a pathogenic insult and remove injured tissue components, thus allowing tissue repair to take place. - It is a component of the innate system. - Classified as acute and chronic inflammation. - Acute inflammation is rapid and usually involves neutrophils and protein-rich exudates from the intravascular space. - Chronic inflammation usually involves ongoing tissue repair and attempts at repair resulting in fibrosis ## **Acute Inflammation** - Usually goes through four main stages: - initiation of the inflammatory process - amplification of the response to curtail the foreign object - destruction of the offending agent - termination of the inflammatory response - Chronic inflammation usually occurs if acute inflammation does not succeed in removing the injurious substance and may take days to weeks - Acute inflammation involves a vascular and cellular phase - **Vascular phase:** Neural based transient vasoconstriction and then vasodilation - Increased blood flow to area (rubor and calor) - Vascular endothelial cell retraction with exudation and leukocyte migration - Leukocytes amplify the process with production of chemical mediators -**Cellular phase:** - The initiation phase involves two factors: a vascular and a cellular phase - Vascular endothelial cell activation with resultant contraction for increased permeability - Endothelial expression of adhesion molecules for leucocyte binding - Leucocyte activation and migration to the site of injury - The leucocytes attempt to remove the offending agent and also initiate the process of repair. - All the various activities are mediated by chemical mediators from cells and plasma ## **Initiation of the Inflammatory Process** - **Presence of pathogen-associated microbial patterns (PAMPs) or danger (damage)-associated molecular patterns (DAMPs)** - These are recognized by pattern-recognition receptors (PRRs). - The PRRs cause gene activation with the release of chemical mediators that cause and maintain inflammation - PRRs include: - Toll-like receptors - Nucleotide oligomerization domain leucine-rich repeat proteins (NOD-like receptors) - Cytoplasmic caspase activation and recruitment domain helicases - C-type lectin receptors ## **Inflammatory Initiators** - **PAMPS** - **Bacteria:** - LPS - Peptidoglycans - Glycolipids - Flagellin - **Virus:** - ssRNA (Single-stranded RNA) - Envelope - **Fungus:** - Zymosan - **DAMPS** - **Cell injury and necrosis:** - ATP - DNA - Uric acid - Proteins - **Tumour Cells:** - ATP - DNA - Uric Acid - Proteins - **ECM Damage:** - Hyaluronan - Hyaluronic acid - Heparin sulfate ## **Summary of the Molecular Pathway of Inflammation** - **Interaction of chemical and cellular mediators:** - Sentinel leukocyte interaction with lipids and then cytokines released followed by chemokines released from the tissue cells - **Pattern recognition molecules:** - DAMPS and PAMPS, as well as PRRs stimulate cell signaling, cytokines and chemokines are released, followed by the activation of coagulation and complement. ## **Cellular Stage** - The cellular stage features tissue edema and neutrophil margination and emigration. ## **Vasoactive and Chemotactic Factors** - **Vasoactive mediators:** - Histamine - Serotonin - Bradykinin - Anaphylatoxins - Leukotrienes/prostaglandins - Platelet-activating factor - Nitric oxide - **Chemotactic factors:** - C5a - Lipoxygenase products: LTB4 - Formylated peptides - Chemokines ## **Chemical Mediators of Inflammation** - **Plasma-derived:** - **Hageman factor activation:** - Clotting/fibrinolytic system - Kallikrein-kinin system - Kinins (bradykinin) - Fibrin split products - **Complement system activation:** - C3a, C5a - **Cell-derived:** - **Mast cell/basophil degranulation:** - Histamine - **Platelets:** - Serotonin - Platelet-activating factor - Prostaglandins - Leukotrienes - **Inflammatory cells:** - Nitric oxide - Platelet-activating factor - Prostaglandins - **Endothelium:** - Nitric oxide - Platelet-activating factor - Prostaglandins ## **Arachidonic Acid Derivatives** - Cell membrane phospholipids are digested by phospholipases to release arachidonic acid. - Arachidonic acid is either metabolized by cyclooxygenase pathway, leading to PGG2, PGH2, Prostacyclin (PGI2) and Thromboxane A2 (TXA2) or by lipoxygenase pathway, leading to 5-HPETE, 5-HETE, Leukotriene A4 (LTA4), Leukotriene B4, Leukotriene C4 (LTC4), Leukotriene D4 (LTD4) and Leukotriene E4 (LTE4). - Other lipoxygenases and HPETEs are also formed. - COX-1 and COX-2 are inhibitors of cyclooxygenase pathway. - Aspirin and indomethacin - Lipoxygenase inhibitors also exist - **Prostacyclin:** Causes vasodilation and inhibits platelet aggregation. - **Thromboxane A2:** causes vasoconstriction and promotes platelet aggregation. - **PGD2 and PGE2:** Both cause vasodilation and increase vascular permeability. - **5-HETE:** Causes chemotaxis. - **Leukotriene B4:** Causes leukotriene receptor antagonists. - **Leukotriene C4, D4 and E4:** Cause bronchospasm and increase vascular permeability. - **Lipoxin A4 and B4:** Inhibit inflammation. - **HETEs:** Cause leukotriene receptor antagonists. ## **Chemical Mediators** - **Interleukins:** - IL-1 - IL-6 - IL-8 - IL-10 - IL-13 - **Growth factors:** - GM-CSF - M-CSF - **Chemokines:** - CC - CXC - XC - CX3C - **Interferons:** - IFNa - IFNB - IFNY - **Proinflammatory cytokines:** - TNFa ## **Recruitment of Cellular Mediators** - **Inflammatory cells:** - **Endothelial cells:** Adhesion molecules, Cytokines, Eicosanoids, Chemokines, Oxygen radicals - **Neutrophils:** Aggregation, Priming - **Acute Phase response:** - Fever, Anorexia, Hypotension, Increased heart rate, Corticosteroid and ACTH release - **Inflammatory mediators:** - Microbes, Necrotic tissue, Macrophage, Dendritic cell, Mast cell - **Recruitment of leukocytes:** - Neutrophils, Monocytes ## **Cellular Mediators of Inflammation** - **Macrophages:** - **Inflammatory:** - Chemokines - Cytokines (IL-1, IL-6, TNFa) - Arachidonic acid metabolites - **Anti-inflammatory:** - Phagocytosis - Anti-inflammatory molecules (IL-1Ra, IL-10, TNFB) - **Innate Antimicrobial:** - Phagocytosis - Antimicrobial molecules (Serine proteases, NADPH oxidase) - NET (Neutrophil extracellular traps) - **Effector:** - Metalloproteinases - Nitric oxide. - Oxidative burst - Phagocytosis - **Accessory:** - Antigen presentation - Costimulatory membrane ligands - Costimulatory cytokines (IL-1) - **Attraction:** - PMN (Polymorphonuclear leukocytes) release MIP-1α, MIP-1β, TNFa, IL-8, IFNγ, IL-17. - **Activation:** - PMN chemokines. - PMN MPO (Myeloperoxidase) and Mac MMR (Macrophage mannose receptor) interaction. - PMN ROS (Reactive oxygen species) - **Differentiation:** - M1 Classical macrophages - Promote Th1 response - Antigen presentation - Promote wound healing - Produce ROS (Reactive oxygen species), IL-12, IL-23, TNFa, IL-1, IL-6, chemokines - Cytotoxicity, Tissue injury - M2 Alternative macrophages - Promote Th2 response. - Tumor-associated macrophages. - Produce IL-4, IL-10, TGFB (Transforming growth factor beta), PDGF (Platelet-derived growth factor), VEGF (Vascular endothelial growth factor), EGF (Epidermal growth factor), arginase. - Immune suppression, Tissue repair - **Neutrophils:** - Phagocytosis - Antimicrobial molecules (Serine proteases, NADPH oxidase) - NET - Activation - **Dendritic cells:** - Attraction - PMN release chemokines - Antigen delivery - PMN deliver antigen to DC - Maturation - Alarmins - High mobility group proteins - Cathelicidins - Direct PMN binding to DC - **T cells:** - Activation - _via_ DC induction - PMN act as APC - Suppression - PMN ROS (Reactive oxygen species) and NO (Nitric oxide) - PMN MAC-1 ## **Resolution** - The inflammatory response is terminated as the offending agent is removed and the process of repair continues. - The process involves gene silencing and reprogramming. - The cells which have been involved in the process of elaborating pro-inflammatory molecules now have their genes silenced. - The genetic apparatus is reprogrammed for the production of anti-inflammatory genes. - Thus there is gradual resolution of the inflammatory process. ## **Anti-Inflammatory Agents:** - **Interleukins:** IL-6, IL-10, IL-11, IL-12, and IL-13 - **Protease inhibitors:** - Secretory lecucocyte proteinase inhibitor (SLP1) - TIMP 1 (Tissue inhibitor of metalloproteinase) - **Lipoxins** - **Glucocorticoids** - **Kininnase** - **Phosphatases** - **Transforming growth factor beta:** A master anti-inflammatory mediator ## **Outcomes of Inflammation** - **Acute inflammation:** - **Usual outcome:** Resolution - **Excessive exudate:** Suppuration - **Excessive necrosis:** Repair and organization, Fibrosis - **Persistence:** Chronic inflammation - **Suppuration:** Abscess - **Repair and organization:** Scar ## **Chronic Inflammation** - **Features:** Continued recruitment of Chronic inflammatory cells - **Continuous tissue injury** due to a prolonged inflammatory response - **An often disordered attempt** to restore tissue integrity. - **The cell types** of chronic inflammation are macrophages and lymphocytes - **The key factor** in chronic inflammation is macrophage activity - **Chronic injury/infection:** - Bacterial and tissue-derived monocyte chemotactic factors - Activated T lymphocytes - Tissue-derived mitogen - Chemotactic factors - Growth factors - Recruitment of circulating monocytes - Proliferation of tissue macrophages - Long-lived tissue macrophages - Increased macrophages - Epithelioid cells - Multinucleated giant cells - Chronic inflammation ## **Cellular Mediators of Chronic Inflammation** - **Macrophages:** - Activated in the classical pathway which promotes granuloma formation. - Activated in the alternative pathway for inflammation resolution. - The classical pathway predominates in chronic inflammation. - **Monocytes:** - GM-CSF - M-CSF - CSF-1 - **Macrophages:** - IFNY, LPS, TNFa - IL-4 - IL-10 - IL-13 - TGFB - **M1 Classical:** - Promote Th1 response - Antigen presentation - Promote wound healing - Produce ROS (Reactive oxygen species), IL-12, IL-23, TNFa, IL-1, IL-6, chemokines - Causing cytotoxicity and tissue injury. - **M2 Alternative:** - Promote Th2 response - Tumor-associated macrophages - Produce IL-4, IL-10, TGFB (Transforming growth factor beta), PDGF (Platelet-derived growth factor), VEGF (Vascular endothelial growth factor), EGF (Epidermal growth factor), arginase. - Causing immune suppression and tissue repair. ## **Lymphocytes** - Associated with chronic Inflammation. - Key cells in humoral and cell-mediated immune responses. - Cytokine production. - Multiple subtypes: - B cell - Plasma cell - Antibody production - Delayed hypersensitivity - Mixed lymphocyte reactivity - T cell - Effector cells - Cytotoxic "killer" cells (K cells) - Helper T cells - Regulatory cells - Suppressor T cells - Cytotoxic natural killer (NK) cell. - Null cell ## **Plasma Cells** - Associated with: - Antibody synthesis and secretion - Chronic Inflammation - Derived from B lymphocytes. ## **Cellular Interactions** - Both cell types interact and affect each other’s activity in different ways. - Macrophages present antigens to T lymphocytes and activate them. - T lymphocytes also recruit and activate macrophages. ## **Fibroblasts** - Key factors in inflammation. - Produce extracellular matrix proteins and chronic inflammation and wound healing mediators. - Mediators include: - PGE2 - CD40 - Matricellular proteins - Extracellular proteins - IL-6 - IL-8 - Cyclooxygenase-2 - Hyaluronan ## **Chronic Granulomatous Inflammation** - Granuloma formation is a protective response designed to isolate an offending agent. - They are nodular aggregations of activated and transformed macrophages (epithelioid cells). - It can either be a foreign body granuloma or an immune granuloma. - INJURY: - Bacterium (e.g., Mycobacterium tuberculosis) - Fungus (e.g., Histoplasma capsulatum) - Foreign particle (e.g., suture) - Inability to digest inciting agent. - Failure of acute inflammatory response. - Persistence of injurious agent. - Cell-mediated immune response. - Sequestration within macrophages. - Recruitment of macrophages, with epithelioid and giant-cell formation - Granuloma formation ## **Granuloma Formation** - CD4+ T cells recruit and organize cells at the site of formation of granuloma. - Chemokines produced by T lymphocytes help in the organization. - CXCL chemokines develop Th1-type granulomas. - CCL chemokines develop Th2-type granulomas. - IFN-γ activate macrophages transforming them to epithelioid cells. - IL-4 and IL-10 are crucial in inhibiting granuloma formation. ## **Causes Of Chronic Granulomatous Inflammation** - **Disease:** - Tuberculosis - Leprosy - Syphilis - Cat-scratch disease - Sarcoidosis - Crohn disease (inflammatory bowel disease) - **Cause:** - Mycobacterium tuberculosis - Mycobacterium leprae - Treponema pallidum - Gram-negative bacillus - Unknown etiology - **Tissue Reaction:** - Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli - Acid-fast bacilli in macrophages; noncaseating granulomas - Gumma: microscopic to grossly visible lesion, enclosing wall of macrophages; plasma cell infiltrate; central cells are necrotic without loss of cellular outline; organisms difficult to identify in tissue - Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon - Noncaseating granulomas with abundant activated macrophages. - Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate. ## **Systemic Manifestations of Inflammation** - Systemic inflammatory response syndrome (SIRS) is the most prominent systemic manifestation of inflammation. It includes: - Activation of the hypothalamic-pituitary-adrenal axis - Leukocytosis - Acute phase response - Fever - Shock ## **Acute Phase Response** - Regulated physiologic reaction that occurs in inflammatory conditions. It includes: - Fever with rigors and chills - Leukocytosis - Decreased appetite and malaise - Altered sleep patterns (somnolence) - Increased pulse and blood pressure. - Decreased sweating. - Changes in plasma levels of acute-phase proteins (which are synthesized in the liver). ## **Acute Phase Proteins** | Protein | Function | |---|---| | Mannose-binding protein | Opsonization/complement activation | | C-reactive protein | Opsonization | | α₁-Antitrypsin | Serine protease inhibitor | | Haptoglobin | Binds hemoglobin | | Ceruloplasmin | Antioxidant, binds copper | | Fibrinogen | Coagulation | | Serum amyloid A protein | Apolipoprotein | | α₂-Macroglobulin | Antiprotease | | Cysteine protease inhibitor | Antiprotease |