Acute chronic Inflammation(1).pdf

Acute and Chronic Inflammation  Inflammation Response of tissues with vasculature to infections and tissue damage The response recruits host defenses (cells and protective molecules) to sites as needed Protective mechanism  Inflammation Acut...

Acute and Chronic Inflammation  Inflammation Response of tissues with vasculature to infections and tissue damage The response recruits host defenses (cells and protective molecules) to sites as needed Protective mechanism  Inflammation Acute vs Chronic Feature Acute Chronic Onset Rapid Slow Cellular infiltrate Neutrophils Macrophage and lymphocytes Tissue injury mild/limited Severe and progressive Local and systemic Prominent Less signs  Inflammation Cardinal signs of inflammation – Heat (calor) – Redness (rubor) – Swelling (tumor) – Pain (dolor) – Loss of function (functio laesa) Have been observed for thousands of years  Inflammation Steps – Offending agent is recognized – Leukocytes and plasma proteins recruited to site – Leukocytes and proteins activated to destroy or eliminate problem – Reaction is terminated – Tissue is repaired  Inflammation Causes – Infections Bacterial, viral, parasitic, fungal, microbial toxins Most importantly medically Each infection type can give a specific response (can be used to ID its etiology) – Tissue necrosis No matter the cause of cell death Molecules released by necrotic cells activate inflammation – Foreign bodies Splinters, dirt, surgical devices Can cause response by self, they damage tissue, or bring microbes Endogenous molecules in large amonts = Urate crystals or cholesterol crystals – Immune reactions Hypersensitivity Autoimmune or allergies  Inflammation Recognition of Microbes or damaged cells – This is the first step in an inflammatory response – Cellular receptors and circulating proteins perform this function Cellular receptors for microbes – Phagocytes and dendritic cells – Toll-like receptors (TLR) are the best defined Found on Plasma membrane and endosomes Recognize pathogen-associated molecular patterns (PAMPs) Sensors for cell damage – All cells have sensors for damaged cells – Damage-associated molecular patterns (DAMPs) Uric acid, ATP, ion concentrations (K+), DNA – Activation of inflammasome which makes IL-1 Circulating Proteins – Complement system – Mannose-binding lectin – Collectins  Inflammation Induced by chemical mediators – Tissue resident macrophages, dendritic cells, mast cells etc. sense problem – Release cytokines and other mediators (plasma proteins) Mediators – Promote efflux of leukocytes – Activate leukocytes These mediators are targets for therapeutics  Mediators of Inflammation They initiate and regulate inflammatory reactions Vasoactive amines, cytokines, lipids, and products of complement system Produced at the site of inflammation or circulating molecules that are activated at the site Activated only by molecules of microbes or necrotic cells Short lived Mediators can stimulate the release of other mediators  Vasoactive amines Histamine Some of the first mediators to be released Stored in granules ready for release – Physical injury (trauma, cold, heat, etc) – Antibody binding to mast cells – Product of complement called anaphylatoxins Histamine – cause dilation of arterioles and increases permeability Arachidonic acid metabolites  Cytokines and chemokines Produced by many cells = many functions Tumor necrosis factor 1 and Interleukin 1 – Promote leukocyte adhesion and migration our of blood vessel Chemokines – 40 different proteins – Increase the affinity of leukocytes integrins – Chemoattractants  Complement system 20+ complement proteins Some increase vascular perm., chemotaxis, etc. Most abundant and important is C3  Changes to Vascular Flow Vasodilation – Result of mediators (histamine) – Earliest manifestations of acute inflammation – Result is increased blood flow = heat and redness Exudate release – After vasodilation = increased permeability – Release of protein rich fluid Loss of fluid and increased caliber cause slowing of blood flow Red blood cells and leukocytes accumulate in area  Exudate vs transudate Exudate = extravascular fluid with high protein concentration and cellular debris – Presence implies increase permeability Transudate = Extravascular fluid low in protein and little of no cellular material Edema Pus  Increased Vascular Permeability Retraction of endothelial cells – Most common mechanism – Histamine, bradykinin, leukotrienes – Within 15 to 30 min from response – Short lived (immediate transient response) – Happens in post capillary venules Endothelial injury – Direct damage = injury, burns, microbial toxin – Neutrophils attracted during response – Can last several hours (delayed prolong response) Transcytosis – Intracellular responses to stimuli – VEGF (vascular endothelial growth factor) Leukocyte Recruitment  Nature of leukocyte infiltrates Neutrophils fast acting but short lived – 6-24 hours Macrophages slow acting but long lived Leukocyte activation  Phagocytosis Three step process – Recognition and attachment of particle – Engulfment and formation of phagocytic vacuole – Killing or degradation of material  Intracellular destruction of engulfed thingys Reactive oxygen species Reactive nitrogen species Lysosomal enzymes This occurs in lysosomes to protect other parts of the cell  ROS NADPH oxidase (phagocyte oxidase) – Forms superoxide Formation of H2O2 and OH radical  RNS Nitric oxide synthase – Nitric oxide = made from arginine NO reacts with superoxide to produce peroxynitrite radical (ONOO) NO also promotes vasodilation  Granule enzymes and extracellular traps Neutrophils and monocytes have granules filled with enzymes that will digest bacteria (lysozyme, histaminase, alkaline phosphatase) These are secreted Neutrophil extracellular traps Made of nuclear chromatin to trap infectious pathogens from spreading  Inflammation Effect is terminated once offending agent is gone – Mediators are short lived, brokendown, dissipated – Leukocytes have short lifespands – anti-inflammatory mechanism activated Tissue is then repaired – Regeneration of surviving cells – Fill in defects with connective tissue  Serous Inflammation Exudation of cell poor fluid  Fibrinous Inflammation Exudate contains fibrin Often inflammation of the lining of body cavities  Purulent Inflammation Pus Abscesses Chronic Inflammation  Chronic inflammation characteristics Infiltration of monocytes Tissue destruction Attempts at healing  Causes of Chronic Inflammation Persistent infection – Delayed type hypersensitivity or granulomatous inflammation Hypersensitivity – Autoimmune, allergic disease Prolong exposure to stimuli – Exogenous and endogenous agents  Cells of Chronic inflammation Macrophages = dominant cell type – Secrete growth factors and cytokines – Kill microbes – Activate other cells Macrophage activation  Macrophage roles Eliminate agents and start healing process Secrete mediators of inflammation Display antigens to T lymphocytes  Lymphocyte roles Part of the adaptive immune response Secrete cytokines  Eosinophil roles Present in infections mediated by IgE and parasites Lyse epithelial cells = tissue damage  Plasma cells and fibroblasts Plasma cells – Secrete antibodies to neutralize toxins Fibroblasts – Produce cytokines, chemokines, and prostaglandins Neutrophils – Usually in acute inflammation – Present with persistent microbes or necrotic cells  Granulomatous Inflammation Characterized by a collection of activated macrophages with T lymphocytes and central necrosis – Epithelioid cells – Giant cells Immune granulomatous – Can’t remove microbe Foreign body granulomas – Foreign body to big  Systemic effects of inflammation Fever – pyrogens Acute-phase proteins – C-reactive protein, fibrinogen, serum amyloid A Leukocytosis – Increase in leukocytes Tissue Repair  Scar Formation Hemostatic plug Inflammation Cell proliferation Remodeling  Angiogenesis Vasodilation Separation of pericyte Migration of endothelial Proliferation of endothelial Remodeling at capillary tips Periendothelial recruitment Stop cell proliferation