CPR2 PDF - Inflammation & Immune Response

Systemic ramifications cytokines are released into the blood Fever induced by pyrogens Pyrogens: Bacterial products, cytokines (IL-1, TNF) - Initiate release of PGE2 from perivascular tissue in hypothalamus - Resets body’s thermostat preventing heat loss - Considered protective Elevated...

Systemic ramifications cytokines are released into the blood Fever induced by pyrogens Pyrogens: Bacterial products, cytokines (IL-1, TNF) - Initiate release of PGE2 from perivascular tissue in hypothalamus - Resets body’s thermostat preventing heat loss - Considered protective Elevated acute-phase proteins Plasma proteins produced in liver - Fibrinogen, C-reactive protein (CRP) in response to IL-6 - serum amyloid A (SAA) in response to IL-1 and TNF Leukocytosis: Induced by IL-1 and TNF Types of inflammation Acute Rapid onset (minutes) Short duration (hours to days) Edema (swelling), redness, pain Emigration of leukocytes (Neutrophils) Chronic May follow acute inflammation if the stimulus persists May be an insidious, low-grade response without acute reaction Long duration (weeks or months) Macrophages & Lymphocytes Proliferation of blood vessels, fibrosis, tissue destruction When the process is excessive or defective, it can cause disability - rheumatoid arthritis, atherosclerosis, lung fibrosis - life-threatening hypersensitivity reactions to insect bites, drugs, and toxins Acute inflammatory steps Recognition: Activation of inflammasome induces production of IL-1 by resident cells: macrophages, dendritic cells, mast cells etc. Two mechanisms Extracellular: receptors on the cell membrane (toll-like), endosomes and cytosol recognize microbial products Intracellular: cytosolic receptors (NOD-like) recognize (DAMPs), - DAMPS: molecules that are liberated or altered due to cell damage Recruitment: inflammatory cells and plasma proteins enter the affected tissue in response to released cytokines Removal: phagocytic cells remove and destroy microbes and dead cells  Regulation: the response ends when it has accomplished its purpose Repair Inflammatory mediators are the target of pharmaceutical anti-inflammatory drugs Anti-inflammatory mediators are naturally secreted to stop a reaction once done Acute inflammatory leukocytes Resident macrophages and dendritic cells (sentinels) React within seconds Detect injury and release IL-1 and TNF-α Initiates the response and recruit leukocytes Detect the threat is gone and secrete TGF-β and IL-10 Mast cells (tissue basophils) React directly Secrete histamine and serotonin Cause vasodilation, vascular permeability Neutrophils React within 6hrs and continue to respond up to 24hrs First responders - More numerous in the blood, respond rapidly to chemokines, attach firmly to the adhesion molecules on endothelial cells short lasting in tissues Circulating monocytes Respond slowly after 24hrs Enter connective tissue and transform into macrophages Proliferate in the tissues - can remain days after injury Secrete growth factors Additional cell presence and contributions: Pseudomonas bacteria: mostly neutrophils Viral infections: lymphocytes may be the first cells to arrive - stay for a few days Some hypersensitivity reactions are mainly by activated lymphocytes, macrophages, and plasma cells Allergic reactions: mostly eosinophils Cardinal signs (local) External manifestations of Inflammation: 1. Redness (rubor) - hyperemia 2. Swelling (tumor) - fluid exudation and hyperemia 3. Heat (calor) - hyperemia 4. Pain (dolor) - release of bradykinin and PGE2 5. Loss of function (functio laesa) – combined effects, mainly swelling and pain (Virchow) Vascular changes Vasodilation Prostaglandins, nitric oxide, histamine Arterioles then capillary beds Causes redness Increased permeability Histamine, serotonin, bradykinin, leukotrienes Causes swelling Two mechanisms: - Immediate transient response (15-30min): Endothelial contraction leading to vascular leakage - Physical injuries (longer duration): Endothelial injury due to necrosis and detachment Increased transport of fluids and proteins through the endothelial cell (VEGF) Swelling (types of fluid leakage) Increased permeability of microvasculature - Enables plasma proteins and leukocytes to leave the circulation Results in increased bood viscosity - larger vessel diameter => slower flow - red cells accumulate centrally pushing the leukocytes peripherally - Transudate (ultrafiltrate): specific gravity 25 g/L - extravascular fluid accumulation high in protein and cell debris - Ex: pus – purulent, rich in leukocytes (mostly neutrophils), dead cells, + microbes Leukocyte recruitment and migration Margination => Rolling => Adhesion to endothelium => Migration across the endothelium => Migration in the tissues IL-1 release by resident cells recruits leukocytes + induces leukocyte differentiation Changes in blood flow cause Leukocytes to express cell-cell recognition molecules Leukocytes react to endothelial adhesion molecules and bind loosely Leukocyte movement is slowed down by selectin receptors on endothelial cells + role on the surface - expressed in response to IL-1 and TNF Endothelial secretions induce morphological change of leukocyte integrins - Integrin – ICAM-1 interactions provide firm adhesion to the endothelium Extension of pseudopod from leukocyte between endothelial cells Leukocyte passes through the basement membrane into CT Leukocyte chemotaxis Leukocytes migrate in response to: Cytokines (TNF, IL-1), chemokines, C3a, C5a, leukotrienes (LTB4), bacterial products & peptides Chemoattractants bind leukocyte receptors => second messenger activation => induce actin polymerization at the leading edge => Cell produces a lamellipodium => Surface receptors attach underlying tissue => myosin accumulation => Actin treadmilling +Cell moves toward the chemoattractant Morphological types of acute inflammation Serous inflammation accumulation of fluid with a low plasma protein and cell content (transudate) Examples: Skin blistering in response to a burn Pleural effusions Pericardial effusions Other serous membrane-lined cavities Fibrinous inflammation The exudate has a high plasma protein content Fibrinogen converted to fibrin and deposited in tissues associated with serous membrane-lined cavities - pleural, pericardial, peritoneal, meninges Fibrin strands form a mat, causing adhesion between adjacent surfaces Can be dissolved by fibrinolysis + removed by macrophages Can lead to scarring - post coronary bypass grafting surgery - does not resolve Clinical correlate - Fibrinous pericarditis Suppurative or purulent inflammation Pyrogenic bacteria: promote purulent inflammation - Ex: Staphylococci, Streptococci (S. pyogenes, S. pneumonia) Pus: exudate in purulent inflammation - rich in neutrophils, liquified debris Abscess: a circumscribed collection of pus ex: Lobar pneumonia, Bronchopneumonia, Acute appendicitis Removal of offending agents Leukocyte activation => receptor changes Recognition and phagocytosis of offending agent Intracellular destruction by ROS, reactive nitrogen species (NO) and lysosomal enzymes mediator production stops Termination of response Mediators stop being released Mediators have a short half-life Neutrophils have a short extravascular life Macrophages release anti-inflammatory agents Anti-inflammatory lipoxins Anti-inflammatory cytokines - ex: transforming growth factor-β (TGF-β) and IL-10 Outcomes of acute inflammation Factors that determine these outcomes: Severity of tissue damage ability of stem cells to regenerate specialized cells Type of agent causing the damage Complete resolution Occurs when CT framework is intact, + the tissue can regenerate Neutrophils and necrotic tissue are phagocytosed (macrophages) - leave the tissue via lymphatic drainage Examples: - after pneumonia, re-growth of alveolar lining cells depends on resident stem cells - Recovery from sunburn (acute inflammatory response in the skin secondary to UV radiation) Resolution + scar formation Occurs in substantial damage to CT Framework or in tissues that can’t regenerate Necrotic debris and acute inflammatory exudate are first removed by macrophages Organization: the defect is filled by granulation tissue ingrowth - appears pink, soft, + granular - amount formed depends on the defect size + intensity of inflammation Granulation tissue is gradually replaced by collagen - forms a fibrous (collagenous) scar Mediators of acute inflammation Plasma proteins: components of the coagulation cascade Fibrinogen, prothrombin, factor VIII, von Willebrand factor acute phase reactants (C-reactive protein..) complement proteins (C3a, C5a..) circulating immunoglobulins (antibodies) Chronic inflammation Chronic inflammation Inflammation, injury, + repair attempts coexist Causes: - Persistent infection by microorganisms that are difficult to eradicate - Mycobacteria, viruses, fungi, and parasites - delayed-type hypersensitivity - granulomatous reaction - Hypersensitivity diseases: Excessive activation of the immune system - autoimmune diseases - rheumatoid arthritis and multiple sclerosis - unregulated immune responses against microbes - e.g. inflammatory bowel disease - reactions triggered against harmless antigens - may show morphologic patterns of mixed acute and chronic inflammation - fibrosis may dominate the late stages - Prolonged exposure to toxins (endogenous or exogenous) silicosis or atherosclerosis Morphological features Infiltration with mononuclear cells - macrophages, lymphocytes, plasma cells Tissue destruction Healing: CT replacement of damaged tissue via angiogenesis + fibrosis. Cells Macrophages: phagocytic APCs - secrete cytokines, eicosanoids + growth factors - destroy foreign invaders - Activate other cells (T lymphocytes) - initiate tissue repair, scar formation, and fibrosis - oval or kidney-bean-shaped nuclei - pale cytoplasm Lymphocytes - amplify and propagate chronic inflammation - dark, round nuclei with a thin basophilic cytoplasm. Plasma cells - Have Purplish cytoplasm and eccentric 'clock face' nuclei. - Differentiated B lymphocytes that produce antibodies Eosinophils - bilobed nuclei - eosinophilic cytoplasmic granules - release granule contents (major basic protein) - attacks parasites Mast cells Neutrophils Fibroblasts - secrete extracellular matrix + collagen - disappear from the tissue over weeks/months Lymphocytes and macrophages interact bidirectionally - Propagate chronic inflammation Chronic granulomatous inflammation Granuloma: a cellular attempt to contain a persistent agent that is difficult to eradicate presence of activated epithelioid macrophages & multinucleate giant cells Epithelioid macrophages fuse - Forms multinucleated giant cells Large mass of cytoplasm containing >20 nuclei 2 types of giant cells: a) Foreign body giant cells: non-immunological agents) Nuclei centrally grouped b) Langhans’ giant cells: immunological agents Nuclei arranged in a horse-shoe at the periphery Ex. Tuberculosis, sarcoidosis, leprosy Inflammation, aging, and exercise Hallmark of aging - Low grade chronic inflammation w/ increased levels of IL-6, TNF-α, CRP and SAA Association between inflammation and chronic diseases unaccustomed exercise at high intensity causes microtears and causes inflammation - initiates repair - Muscle adapts with repeated sessions Regular cardiovascular exercise diminishes overall inflammatory markers despite increases in Il-6 Inverse dose-response relationship with physical activity + systemic inflammatory markers - The longer and higher intensity the exercise, the more reduced the inflammatory markers - moderate amounts of physical activity in people 60+ years => reduction in CRP Clinical - sunburn: Tuberculosis Granuloma