Inflammation Dr. Najla Aldaoud, MD School of Medicine, JUST Inflammation The body is exposed to wide range of causes of injury (trauma, infection, heat / cold, infarction, radiation, chemicals). How does the body protect itself against injury? Inflammation Non-specific mechanisms: Mechanical barriers skin barrier acid in stomach mucus and cilia in lungs Inflammation Phagocytosis Specific mechanisms: specific immune response humoral (antibody) mediated cell-mediated. Inflammation Definition: A dynamic process of chemical and cytological reactions that occur in response of vascularized living tissue to stimuli that cause cell injury. Inflammation results in: accumulation of leukocytes, and fluid in extravascular tissue. systemic effects. Inflammation is a protective response. Inflammation Inflammation is a protective response that aims to: clear the body of the cause of the cell injury. destroy, dilute or isolate the injurious agent (microbes, toxins). Eliminate the consequences of that injury of the necrotic cells and tissues. Paves the way for repair Participants of Inflammation Inflammatory responses involve an interaction of: Blood vessels (endothelial cells and smooth muscles of vessels) White blood cells and platelets Neutrophils, monocytes, basophils lymphocytes, eosinophils. Plasma proteins and chemical mediators: Coagulation / fibrinolytic system, kinin system, complement system Participants of Inflammation (Cont..) Inflammatory responses involve also an interaction of: Extracellular matrix and stromal cells Mast cells, fibroblasts, macrophages & lymphocytes Structural fibrous proteins, adhesive glycoproteins, proteoglycans, basement membrane Participants of Inflammation Inflammation Inflammation and repair may have potentially harmful outcomes such as digestion of normal tissues, swelling, and inappropriate inflammatory response. Rheumatoid arthritis. Life threatening hypersensitivity reactions. Fibrous scarring after pericarditis. Inflammation Nomenclature -itis (- after name Appendix Dermis Gallbladder Duodenum Meninges of tissue) e.g. Appendicitis Dermatitis Cholecystitis Duodenitis Meningitis, etc Inflammation Inflammation is divided into acute and chronic patterns. Acute Inflammation Acute inflammation is a non-specific immediate and early response to tissue damage. It begins within seconds and lasting hours to several days, or longer if the cause persists. It aims to mediate local defences, destroy any infective agents and remove debris. Causes: any cause of cell injury. Causes of Acute Inflammation Infections (bacteria, fungal, viruses, and parasites). Physical agents (heat, cold, burns, radiation, and trauma). Chemicals (acids, alkali, bacterial toxins, metals, and caustic substances). Necrotic tissue (infarction) All types of immunologic reactions, i.e., hypersensitivity (contact with some substances), autoimmune reactions Local Signs of Acute Inflammation Heat Redness Swelling Pain Loss of function Features of Acute Inflammation Vascular changes Cellular events Emigration of leukocytes from microvessels Acute Inflammation Vascular Changes Transient vasoconstriction Vasodilatation Slowing of the circulation and stasis Leukocytic margination Acute Inflammation Vascular Changes Transient vasoconstriction of arterioles disappears within 3-5 seconds in mild injuries may last several minutes in more severe injury (burn). Acute Inflammation Vascular Changes Vasodilatation: 1st involves the arteriole and it is the cause of heat and redness). Increased blood volume lead to increased local hydrostatic pressure leading to transudation of protein -poor fluid into the extravascular space. Acute Inflammation Vascular Changes Slowing of the circulation due to increased permeability of the microvasculature, this leads to outpouring of protein-rich fluid in the extravascular tissues. This results in concentration of the red cells in small vessels and increased viscosity of the blood (stasis: dilated small vessels packed with red cells). Acute Inflammation Vascular Changes Persistence of stasis leads to peripheral orientation of leukocytes (mainly neutrophils) along the vascular endothelium [leukocytic margination]. leukocytes 1st stick transiently then more strongly, then they migrate through the vascular wall into the interstitial tissue [emigration]. Features of acute inflammation Components of exudate Fluid. Fibrin (insoluble): derived from the plasma protein fibrinogen (soluble), also important in clotting Cells: neutrophils predominate (6-72 hours), also macrophages (involved slightly later: 48+ hours) Exudate arises in inflammation due to increased vascular permeability and has a high protein content. Transudate results from hydrostatic imbalances between vessel and extravascular tissues, vascular permeability is normal, has a low protein content.) Features of Acute Inflammation Features of acute inflammation Acute Inflammation Leukocyte Cellular Events Margination, rolling and adhesion Transmigration between endothelial cells Migration in the interstitium toward the site of stimulus (chemotaxis activation) Phagocytosis and degranulation Release of leukocyte products and Neutrophil Margination Neutrophil Margination Effects of Chemotactic Factors on Endothelial Cells Effects of Chemotactic Factors on Leukocytes Diapedesis Leukocyte Cellular Events The Process of Extravasation of Leukocytes Selectins and their carbohydrate counterligands mediate leukocyte binding and rolling. Leukocyte integrins and their ligands mediate firm adhesion. The Process of Extravasation of Leukocytes (Cont..) Chemokines play a role in firm adhesion by activating integrins on the leukocyte cell surface. The leukocytes are directed by chemoattractant gradients to migrate across the endothelium, and through the extracellular matrix into the tissue. The Process of Extravasation of Leukocytes Lobar Pneumonia Chemotaxis Migration of cells along a chemical gradient Chemotactic factors: Soluble bacteial products, e.g. N-formylmethionine termini Complement system products, e.g. C5a Lipooxygenase pathway of arachidonic acid metabolism, e.g. LTB4 Cytokines, e.g. IL-8 Effects of Chemotactic Factors on Leukocytes Stimulate locomotion Degranulation of lysosomal enzymes Production of AA metabolites Modulation of the numbers and affinity of leukocyte adhesion molecules Effects of Chemotactic Factors on Endothelial Cells Effects of Chemotactic Factors on Leukocytes Generation of AA Metabolites Phagocytosis The process of ingestion and digestion by cells of solid substances, e.g., other cells, bacteria, necrotic tissue or foreign material. Steps of phagocytosis: Recognition, attachment and binding to cellular receptors. Engulfment Fusion of phagocytic vacuoles with lysosomes Killing or degradation or ingested material Phagocytosis How Do Leukocytes Kill Infectious Agents Oxygen burst products (free radical) Lysosomal enzymes Bactericidal permeability increasing protein Major basic protein Defensins General principles for chemical mediators Mediators derive from plasma or by local production from cells. Most mediators perform their activity by initially binding to specific receptors on target cells. However, some have direct enzymatic or toxic activities. Mediators may stimulate target cells to release secondary effector molecules, which may have activities similar (amplifying) or opposing (counterregulating) the initial stimulus. Slide 3.23 Slide 3.30 Outcomes of Acute Inflammation Complete resolution Healing by scarring or fibrosis Abscess formation Progression to chronic inflammation Outcomes of Acute Inflammation Complete resolution Occurs when the injury is limited or short-lived and when the tissue is capable of regeneration Outcomes of Acute Inflammation (Cont..) Scarring or fibrosis Occurs when there is destruction. substantial tissue when the inflammation occurs in tissue not capable of regeneration. there is extensive fibrinous exudate that cannot completely absorbed. Outcomes of Acute Inflammation (Cont..) Abscess formation: may occur in the setting of certain bacterial or fungal infection (pyogenic or “pus forming”) Progression to chronic inflammation Morphologic Appearance of Acute Inflammation Catarrhal Acute inflammation + mucous hypersecretion (e.g. common cold) Serous Abundant protein-poor fluid with low cellular content, e.g. skin blisters and body cavities Fibrinous: Accumulation of thick exudate rich in fibrin, may resolve by fibrinolysis or organize into thick fibrous tissue (e.g. pericarditis) Burn Blister Fibrinous Pericarditis Morphologic Appearance of Acute Inflammation (Cont..) Suppurative (purulent): Pus: Creamy yellow or blood stained fluid consisting of neutrophils, microorganisms & tissue debris e.g. acute appendicitis Abscess: Focal localized collection of pus Empyema: Collection of pus within a hollow organ Ulcers: Defect of the surface lining of an organ or tissue, mostly GI tract or skin Subcutaneous Abscess Lung Abscess Foot Ulcer Chronic inflammation Chronic inflammation Chronic inflammation is a process in which ongoing inflammation and tissue damage proceed at the same time as attempts at healing, seen as scarring. It aims to eradicate and/or contain the harmful agent and heal areas of tissue damage. It last longer duration and can persist, sometimes for years, until the damaging stimulus is eradicated. Chronic inflammation Chronic inflammation may follow acute inflammation because of persistence of the injurious agent or interference with the normal process of healing. Changes are superimposed upon and/or replace those of acute inflammation several days after onset. In some cases it has an insidious onset: infections (TB) autoimmune disease (rheumatoid arthritis) repeated or prolonged exposure to toxic (asbestos). Chronic inflammation • Is characterized histologically by: •Infiltration with mononuclear (“chronic inflammatory”) cells including macrophages, lymphocytes, and plasma cells •Tissue destruction (induced mainly by inflammatory cells) •Repair involving new vessel formation (angiogenesis) and fibrosis. Causes of Chronic Inflammation Follow acute inflammation Persistence of injurious agent Interference in the normal process of healing Causes of Chronic Inflammation (Cont..) Begin insidiously as a slow response to various agents: Microorganisms that are intracellular (viruses) or are of low direct pathogenicity, but evoke a delayed immune response (mycobacteriatubercle bacillis) Prolonged exposure to potentially toxic agents. E.g., (silicosis) Autoimmune diseases: immune response to self antigens and tissues (which are constantly renewed) e.g., rheumatoid arthritis. Cell Types in Chronic Inflammation Macrophages Plasma cells Eosinophils Lymphocytes Chronic Inflammation Cell types Plasma cells: Are the terminally differentiated B-cell lymophocytes. Produce antibodies directed against antigens in the inflammatory site Lymphocytes: antibodies and cell mediated immunologic reactions non-immune-inflammation reciprocal relationship to macrophages Chronic Inflammation Cell types Eosinophils: immunologic reactions mediated by IgE (allergy) Seen in parasitic infections respond to chemotactic agents derived largely from mast cells contain major basic protein: toxic to parasites and lead to lysis of mammalian epithelial cells Chronic Granulomatous Inflammation Granulomatous inflammation is a specific type/pattern of chronic inflammation characterised by the presence of activated macrophages that either become ‘epithelioid’ in appearance or become giant multinucleate cells. Tuberculosis, leprosy, schistosomiasis, sarcoidosis, Crohn’s disease, reactions to foreign material (e.g. suture), Chronic Granulomatous Inflammation Characterized by formation of granulomas: 0.5 - 2 mm. Nodules composed of : Modified macrophages (epithelioid cells) Langhan’s or foreign body giant cells Fibroblasts, plasma cells, lymphocytes, neutrophils Necrosis is present (necrotizing granulomatous inflammation) with certain causes e.g TB, but not in sarcoidosis for example. The patterns of granulomatous inflammation vary depending on the cause Role of lymphatic & Lymph Nodes in Inflammation Represents a second line of defense Delivers antigens and lymphocytes to the central lymph nodes Lymph flow is increased in inflammation May become involved by secondary inflammation (lymphangitis, reactive lymphadenitis) Systemic effects of inflammation Fever, chills acute phase reactions: increased slow wave sleep decreased appetite increased degradation of protein hypotension and other hemodynamic changes synthesis of acute phase proteins by the liver: C-reactive proteins and serum amyloid A complement and coagulation proteins Systemic effects of inflammation (cont.) leukocytosis (neutrophilia, lymphocytosis, eosinophilia) leukopenia (typhoid fever, viruses, rickettsia, &certain protozoa) Role of IL-1, and TNF