Inflammation Handout PDF

Inflammation Gerard Leaño Lamayra, MD, FPSP Anatomic and Clinical Pathology General Considerations Inflammation - reaction of a tissue and its microcirculation to a pathologic insult; characterized by the generation of inflammatory mediators and movement of fluid and leucocytes. Clinica...

Inflammation Gerard Leaño Lamayra, MD, FPSP Anatomic and Clinical Pathology General Considerations Inflammation - reaction of a tissue and its microcirculation to a pathologic insult; characterized by the generation of inflammatory mediators and movement of fluid and leucocytes. Clinical signs: (1) Rubor (redness) (2) Calor (heat) (3) Tumor (swelling) (4) Dolor (pain) (5) Loss of function (functio laesa) General Considerations John Hunter – modern understanding on the vascular basis of inflammation. Rudolf Virchow - described that inflammation is a reaction to prior tissue injury. Thomas Lewis - described the importance of chemical mediators in the inflammatory response. Primary purpose of inflammatory response -eliminate the pathologic insult and remove injured tissue components. What inflammation accomplishes: (1) regeneration of normal tissue architecture (2) formation of scar tissue to replace those that cannot be repaired Further extension of injury or the effects of the inflammatory response may lead to loss of function of the organ or tissue. Stages in inflammatory process (1) Initiation of the mechanisms responsible for the localization and clearance of foreign substances and injured tissues; stimulated when injury to tissues has occurred. (2) Amplification of the inflammatory response; both soluble mediators and cellular inflammatory systems are activated. (3) Termination of the inflammatory response; accomplished by specific inhibitors of inflammatory mediators. SEQUENCE OF EVENTS Normal histology  Vasodilatation  Increased vascular permeability  Leakage of exudate  Margination, rolling, adhesion of WBCs  Transmigration (diapedesis)  Chemotaxis SEQUENCE OF EVENTS  PMN (neutrophil) Activation  PHAGOCYTOSIS: Recognition, Attachment, Engulfment, Killing (degradation or digestion)  Termination 100% RESOLUTION, SCAR, or CHRONIC INFLAMMATION are the three possible outcomes SEQUENCE OF EVENTS INFLAMMATION -earliest response following tissue injury occurs within the microvasculature at the level of capillary and post-capillary venule. -changes in the structure of the vascular wall lead to the following: (i) loss of endothelial cell integrity (ii) leakage of fluid and plasma components (iii) emigration of red and white blood cells from the intraluminal space into the extravascular tissue ACUTE INFLAMMATION “PROTECTIVE” RESPONSE NON-specific Hallmarks of acute inflammation: 1. Accumulation of fluid and plasma components in affected tissues 2. Vascular stimulation of platelets 3. Presence of polymorphonuclear leucocytes ACUTE INFLAMMATION Major events: 1. Changes in vascular flow and caliber 2. Increase vascular permeability 3. Leucocyte exudation ACUTE INFLAMMATION Neutrophil Polymorphonuclear Leukocyte (PMN) STIMULI for acute inflammation INFECTIOUS agents PHYSICAL agents CHEMICAL agents Tissue Necrosis Foreign bodies Immune “responses”, or “complexes” Vascular Changes in acute inflammation Changes in vascular flow and caliber Increased vascular permeability INCREASED vascular permeability Edema- manifested as swelling; movement of fluid into the extravascular space which exceeds the clearance ability of the lymphatics. inflammatory edema – due to alterations in the anatomy and function of the microvasculature promoting fluid accumulation in tissues. The post-capillary venule is the primary site at which vasoactive mediators induce endothelial changes including endothelial cell contraction and gap formation Some definition of terms: edema- accumulation of fluid within the extravascular component and interstitial tissues. effusion – excess body fluid in the cavities of the body, i.e. peritoneum, pleura. transudate – excess fluid with low protein content (sp. gr. 20 components, in circulating plasma Multiple sites of action, but LYSIS is the underlying theme KININ SYSTEM BRADYKININ is KEY component ALSO from circulating plasma ACTIONS  Increased permeability  Smooth muscle contraction, NON vascular  PAIN CLOTTING FACTORS Also from circulating plasma Coagulation, i.e., production of fibrin Fibrinolysis EICOSANOIDS (Arachidonic acid derivatives) Part of cell membranes 1) Prostaglandins (including thromboxanes) 2) Leukotrienes 3) Lipoxins -multiple actions at many levels Prostaglandins (thromboxanes included) Pain Fever Clotting mechanism Leukotrienes Chemotaxis Vasoconstriction Increased permeability Lipoxins INHIBIT chemotaxis Vasodilatation Counteract actions of leukotrienes Platelet-Activating Factor (PAF) Phospholipid From MANY cells, like eicosanoids ACTIVATE PLATELETS, powerfully CYTOKINES/CHEMOKINES CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation. TNFα, IL-1, by macrophages CHEMOKINES are small proteins which are attractants for PMNs. NITRIC OXIDE Potent vasodilator Produced from the action of nitric oxide synthetase from arginine LYSOSOMAL CONSTITUENTS PRIMARY SECONDARY also called also called SPECIFIC AZUROPHILIC, or non-specific Myeloperoxidase Lactoferrin Lysozyme Lysozyme Acid hydrolases Alkaline phosphatase Collagenase FREE RADICALS O2– (superoxide) H2O2 (peroxide) - OH (hydroxyl radical) VERY DESTRUCTIVE!!! NEUROPEPTIDES Produced in CNS (neurons) Substance P Neurokinin A OUTCOMES OF ACUTE INFLAMMATION (1) 100% complete RESOLUTION (2) SCAR (3) CHRONIC inflammation CHRONIC INFLAMMATION -may be a sequel to acute inflammation or an autoimmune response to a foreign antigen. -occur when inflammatory response is unable to eliminate the injurious agent or restore injured tissue to its normal state. -primarily serves to contain and remove a pathological agent or process within a tissue. -frequently observed in conjunction with reparative responses: namely, granulation tissue and fibrosis. Cellular components of chronic inflammation Lymphocytes Macrophages (aka, histiocytes) Plasma cells Eosinophils Mast cells CHRONIC INFLAMMATION MONOCYTE Lymphocyte MACROPHAGE HISTIOCYTE CAUSES of CHRONIC INFLAMMATION 1) PERSISTENCE of infection 2) PROLONGED EXPOSURE to insult 3) AUTO-IMMUNITY Chronic inflammation as a PRIMARY RESPONSE -the presence of cells characteristic of chronic inflammation does not necessarily imply existence of a persistent inflammation. -a chronic inflammatory infiltrate is a primary response to parasitic infections, certain immune diseases, parasitic infestations, and malignant tumors. GRANULOMATOUS INFLAMMATION -the mechanism for dealing with indigestible substances. -the principal cells involve are macrophages and lymphocytes. after amassing substances that they cannot ingest, the macrophages lose their motility and accumulate at site of injury. they undergo changes in structure that transforms them into epithelioid cells. GRANULOMATOUS INFLAMMATION -nodular collections of epithelioid cells form granulomas. -granulomas are the morphological hallmark of granulomatous inflammation. small collections of epithelioid cells surrounded by a rim of lymphocytes; they are also populated by multinucleated giant cells formed by cytoplasmic fusion of macrophages. GRANULOMA 4 COMPONENTS Fibroblasts Lymphocytes HISTIOCYTES “GIANT” cells GRANULOMATOUS INFLAMMATION Langhans giant cells –when the nuclei are arranged around the periphery of the cell in a horseshoe pattern. GRANULOMATOUS INFLAMMATION Foreign body giant cells – when a foreign pathogenic agent or other indigestible material is identified within the cytoplasm of multinucleated giant cell. GRANULOMATOUS INFLAMMATION -the fate of granulomatous reaction is influenced by the cytotoxicity of the inciting agent and its immunogenicity. -the typical tissue response elicited by: (1) fungal infections (2) tuberculosis (3) leprosy (4) schistosomiasis (5) presence of foreign material, i.e. suture, talc (6) sarcoidosis MORPHOLOGIC PATTERNS in acute and chronic inflammation 1. Serous inflammation 2. Fibrinous inflammation 3. Suppurative or purulent inflammation 4. Ulcer Serous inflammation -marked by an outpouring of thin fluid from the blood serum or secretions of mesothelial cells lining the body cavities (an effusion). Fibrinous inflammation -fibrinous exudates develop when the vascular leaks are large enough or there is a procoagulant stimulus in the interstitium. -characteristic inflammation of body cavities. Suppurative inflammation -characterized by the production of large amount of pus consisting of neutrophils, necrotic cells, and edema fluid. Ulcers -local defect, or excavation, of the surface of an organ or tissue that is produced by sloughing (or shedding) of the inflammatory necrotic tissue. Systemic Manifestations of Inflammation -local injury may result in systemic effects that can be debilitating: (i) entrance of pathogen in the bloodstream resulting in systemic activation of mediator systems in the plasma and inflammatory cells (sepsis) (ii) severe local injury resulting in the release of cytokines into the circulation causing systemic effects Systemic Manifestations of Inflammation -prominent systemic manifestations include: (1) fever (2) shock (3) leucocytosis (4) leucopenia (5) acute phase response Fever -clinical hallmark of inflammation. -bacteria, viruses, and injured cells stimulate the production of endogenous pyrogens (IL-1, Il-6, TNF-α) released by macrophages which stimulates prostaglandin synthesis in the hypothalamic thermoregulatory centers altering the “thermostat” that controls the body temperature. Shock -under massive injury or infection spreading to the blood, systemic release of TNF-α cause systemic vasodilatation, increased vascular permeability with vascular volume loss leading to hypotension and shock. -systemic activation of coagulation pathways may occur generating microthrombi throughout the body with consumption of clotting factors predisposing to bleeding. Leucocytosis -increase in the number of circulating leucocytes. -presents as a 2-3x increase mainly neutrophils. -release of mediators accelerating release of PMNs from the bone marrow. -production of colony-stimulating factors induce proliferation of bone marrow hematopoietic precursor cells. Leucocytosis Neutrophilia – most common in association with bacterial infections and tissue injury. Lymphocytosis – usually accompany viral infections. Eosinophilia – associated with parasitic infestations and allergic reactions. Leucopenia -absolute decrease in circulating white cell count. -seen in patient with chronic debilitating diseases, typhoid fever, and certain viral and rickettsial infections. Acute phase response -characterized clinically by fever, leucocytosis, decreased appetite, altered sleep patterns. -changes in the plasma levels of acute phase proteins. group of molecules synthesized in the liver and release in the circulation in response to acute inflammatory response, e.g. C-reactive protein, haptoglobulin, fibrinogen. -reflected in accelerated erythrocyte sedimentation rate (ESR) which is used as qualitative index to monitor activity of many inflammatory processes.