Inflammation PDF

INFLAMMATION At the end of the unit, the student must be able to: 1. explain terms related to inflammation and repair. 2. discuss the importance of body response to inflammation. 3. identify the clinical manifestations in the presence of inflammation. 4. identify the causes of inflammat...

INFLAMMATION At the end of the unit, the student must be able to: 1. explain terms related to inflammation and repair. 2. discuss the importance of body response to inflammation. 3. identify the clinical manifestations in the presence of inflammation. 4. identify the causes of inflammation and its preventive measures and possible management  May also be harmful – Hypersensitivity reactions – Organ damage  General Characteristics 2 main components: – vascular wall response – inflammatory cell response Effects mediated by circulating plasma proteins and by factors produced locally by vessel wall or inflammatory cells. Terminated when offending agent is eliminated and the secreted mediators are removed.  Patterns Acute Inflammation Chronic Inflammation Early onset Later onset Short duration Longer duration Involves fluid exudation Induces blood vessel proliferation and scarring Polymorphonuclear cell Lymphocytes and emigration macrophages  5 Classic Clinical Signs Heat /Calor Redness/Rubor Edema/Tumor Pain/Dolor Loss of Function/ Functio Laesa ACUTE INFLAMMATION  3 Major Components Alteration in vascular caliber Structural changes in the microvasculature Leukocyte emigration from blood vessels and accumulation at the site of injury  VASCULAR CHANGES Normal fluid exchange depends on an intact endothelium and is modulated by: – Hydrostatic Pressure (Kicking force) – Plasma colloid osmotic pressure (keeping force)  Increased Vascular Permeability – Formation of venule intracellular endothelial gaps – Direct endothelial injury – Increased transcytosis – Leakage from new blood vessels  CELLULAR EVENTS Leukocyte Extravasation – Margination, Rolling, Adhesion to the endothelium – Transmigration across the endothelium (Diapedesis) – Migration in interstitial tissues toward a chemotactic factor  Chemotaxis Process by which leukocytes are attracted to and move toward an injury. Mediated by diffusible chemical agents. Phagocytosis 3 Steps: Recognition and binding Engulfment Killing and degradation  Products Released by Leukocytes (Induce Tissue Injury) Lysosomal Enzymes Oxygen-derived active metabolites Products of arachidonic acid metabolism Termination of the Acute Inflammatory Response Inflammation must be regulated because of its inherent capacity to cause damage. As inflammation develops, the process also triggers stop signals – Switching production of arachidonate metabolites to anti-inflammatory forms – Production of anti-inflammatory cytokines (TGF- β)  CHEMICAL MEDIATORS Mediate the vascular and cellular events of inflammation Derived from plasma or from cells Induced primarily by microbial products Most are short-lived also have potentially harmful effects  Plasma Proteins 3 interrelated plasma-derived mediators play key roles in inflammation 1. Complement 2. Kinin 3. Clotting Systems  Complement System Biologic functions of the Complement System 1. Inflammation C3a and C5a – stimulate histamine release → increased vascular permeability, vasodilation C5a – powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils. – activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes, causing further release of inflammatory mediators. 2. Phagocytosis C3b when fixed to a microbial cell wall, act as an opsonin and promote phagocytosis 3. Cell lysis deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis) of the cells.  Kinin System Converts prekallikrein to kallikrein Kallikrein – Has chemotactic activity – Causes neutrophil aggregation – produce Bradykinin (causes vasodilation and increased vascular permeability)  Clotting System Divided into 2 interrelated systems that converge to activate a hemostatic mechanism Fibrinopeptides – Induce vascular permeability – Chemotactic for leukocytes Thrombin – Has inflammatory properties – Causes increased leukocyte adhesion to endothelium  Factor XIIa – can also induce the fibrinolytic system, producing plasmin – Plasmin contributes to inflammation by cleaving C3 to produce C3 fragments, forming FSPs that increase vascular permeability.  Arachidonic Acid Metabolites Cyclooxygenase – Generates prostaglandins and thromboxanes Lipoxygenase – Produces leukotrienes and lipoxins  Platelet-Activating Factor Produced by mast cells and other leukocytes functions – platelet aggregation and release – Bronchoconstriction – Vasodilation – Increased vascular permeability – Increased leukocyte adhesion – Leukocyte chemotaxis  Cytokines and Chemokines Cytokines – Proteins produced by activated lymphocytes and macrophages – Modulate the function of other cell types Chemokines – Cytokines that also stimulate leukocyte movement  Tumor Necrosis Factor and Interleukin 1 Major cytokines mediating inflammation Produced by activated macrophages  Chemokines Act as chemoattractants and activators for leukocytes they stimulate leukocyte recruitment in inflammation control the normal migration of cells through various tissues.  Nitric Oxide a.k.a. endothelium-derived relaxation factor Causes relaxation by relaxing smooth muscles Also inhibits platelet aggregation and adhesion and kills certain microbes and tumor cells (via free radical formation)  Oxygen-Derived Free Radicals Effects: – Endothelial cell damage – Injury to multiple cell types (tumor cells, red cells, parenchymal cells)  Protect tissues from ROS – Ceruloplasmin – Transferrin – Superoxide dismutase – Catalase – Glutathione peroxidase OUTCOMES OF ACUTE INFLAMMATION  MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION morphologic hallmarks: – dilation of small blood vessels – slowing of blood flow – accumulation of leukocytes and fluid in the extravascular tissue  Special Morphologic Patterns Serous Inflammation – Reflected by tissue fluid accumulation – indicates a modest increase in vascular permeability – Effusion: when in the pleural, peritoneal and pericardial cavities  Fibrinous Inflammation – More marked increase in vascular permeability – With exudates containing large amounts of fibrinogen. – The fibrinogen is converted to fibrin through coagulation system activation  Suppurative Inflammation – Production of purulent exudate consisting of leukocytes and necrotic cells – Abscess: localized collection of purulent inflammatory tissue accompanied by liquefactive necrosis  Ulcers – Local erosions of epithelial surfaces – Produced by sloughing of inflamed necrotic tissue. CHRONIC INFLAMMATION  A prolonged process in which active inflammation, tissue destruction, and attempts at healing may all be proceeding simultaneously.  Characterized by: – Infiltration with mononuclear inflammatory cells (macrophages, lymphocytes, plasma cells) – Tissue destruction – Attempts at healing by connective tissue replacement accomplished by vascular proliferation (angiogenesis) and fibrosis  Mononuclear Cell Infiltration Macrophages: – Dominant cellular players in chronic inflammation – Derive from circulating monocytes induced to emigrate across the cell membrane by chemokines. In the extravascular tissue, monocytes transform into macrophages.  Other Cells in Chronic Inflammation Lymphocytes – Mobilized in antibody- and cell-mediated immune reactions – Activates macrophages, influence T (and B) lymphocyte function – PLASMA CELLS: produce antibodies  Eosinophils – Characteristic of immune reactions mediated by IgE and in parasitic infections. – Granules contain MBP (toxic to parasites but also lyses mammalian epithelium)  Mast Cells – Participate in both acute and chronic inflammation – In acute reactions, binding of antigens to IgE Abs leads to mast cell degranulation and histamine release (anaphylactic reactions)  Granulomatous Inflammation Granuloma – a cellular attempt to contain an offending agent that is difficult to eradicate. – strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues. – Examples: Tuberculosis Sarcoidosis cat-scratch disease lymphogranuloma inguinale Leprosy brucellosis Syphilis some mycotic infections berylliosis, reactions of irritant lipids some autoimmune diseases  2 Types of Granulomas Foreign body granulomas – incited by relatively inert foreign bodies. – Epithelioid cells and giant cells are apposed to the surface of the foreign body – The foreign material can usually be identified in the center of the granuloma Foreign body granuloma  Immune granulomas – Formed by immune T-cell mediated responses to persistent antigens. – IFN-y from activated T cells causes macrophage transformation to epithelioid cells and multinucleate giant cells. – prototype : Tuberculosis granuloma is referred to as a tubercle. characterized by the presence of central caseous necrosis Tuberculous granuloma  Systemic Effects of Inflammation Acute Phase Response – Systemic changes associated with inflammation – In severe cases: Systemic Inflammatory Response Syndrome (SIRS) – Response to cytokines produced by either bacterial products or by other inflammatory stimuli  Fever – Produced in response to pyrogens, substances that stimulate prostaglandin synthesis in the hypothalamus. PGE2 stimulates intracellular second signals (cAMP) that reset the temperature set point.  Acute-phase proteins – Plasma proteins, mostly synthesized in the liver, whose synthesis increases in response to inflammatory stimuli – C-reactive Protein (CRP), Fibrinogen, Serum amyloid A (SAA) – CRP and SAA bind to microbial cell walls May act as opsonins Fix complement also bind chromatin, possibly aiding in the clearing of necrotic cell nuclei. – Fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly (basis for measuring ESR)  Hepcidin: iron-regulating peptide Chronically elevated plasma concentrations of hepcidin reduce the availability of iron and are responsible for the anemia associated with chronic inflammation  Leukocytosis – Occurs by accelerated release of bone marrow cells (typically with a shift to the left) – Prolonged infection also induces proliferation of bone marrow precursors due to the increased WBC production – Leukocyte counts: 15,000-20,000 cells/uL May reach 40,000-100,000 cells/uL (Leukemoid Reaction) – Bacterial Infections: Neutrophils – Viral infections: Lymphocytes – Parasitic infections and allergic reactions: Eosinophils  Other Manifestations of the Acute Phase Response – Increased pulse and blood pressure – Decreased sweating – Rigors – Chills – Anorexia – Somnolence – Malaise  In sepsis: – Large amounts of organisms and endotoxin in the blood stimulate the production of enormous quantities of several cytokines (TNF and IL-1) – High levels of these cytokines result in a clinical triad of DIC, Hypoglycemia and Cardiovascular Failure  Consequences of Defective Inflammation results in increased susceptibility to infections delayed wound healing, because inflammation is essential for clearing damaged tissues and debris  Consequences of Excessive Inflammation Basis of many categories of human disease – Allergies individuals mount unregulated immune responses against commonly encountered environmental antigens – Autoimmune diseases immune responses develop against normally tolerated self-antigens disorders in which the fundamental cause of tissue injury is inflammation  Inflammation also plays a role in the pathogenesis of diseases that are not primarily disorders of the immune system – atherosclerosis and ischemic heart disease – Alzheimer disease  Prolonged inflammation and the fibrosis that accompanies it are also responsible for much of the pathology in many infectious, metabolic, and other diseases.  Factors that causes poor wound healing Infection Diabetes. Nutritional status has profound effects on repair; protein malnutrition and vitamin C deficiency, for example, inhibit collagen synthesis and retard healing. Glucocorticoids (steroids) have well-documented antiinflammatory effects, and their administration may result in weak scars because they inhibit TGF-β production and diminish fibrosis. In some instances, however, the anti-inflammatory effects of glucocorticoids are desirable. For example, in corneal infections, glucocorticoids may be prescribed (along with antibiotics) to reduce the likelihood of opacity due to collagen deposition. Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart (dehisce). Poor perfusion, resulting either from arteriosclerosis and diabetes or from obstructed venous drainage (e.g., in varicose veins), also impairs healing. Foreign bodies such as fragments of steel, glass, or even bone impede healing. The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of cells capable of proliferating; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of nondividing cells must inevitably result in scarring; such is the case with healing of a myocardial infarct.  The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of cells capable of proliferating; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function.  The location of the injury and the character of the tissue in which the injury occurs also are important. For example, in inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities), small exudates may be resorbed and digested by the proteolytic enzymes of leukocytes, resulting in resolution Thank You!