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Chapter 5 Innate Immunity: Inflammation and Wound Healing Innate Immunity: First Line of Defense  Physical barriers—epithelial cells of skin, GI, GU & respiratory tracts remove pathogens by sloughing off dead skin, cilia—mediated coughing, sneezing, vomiting, & urination  Epithelial—derived chemicals that protect against infections—mucus, perspiration, saliva, tears, and earwax which create an acidic environment  Normal flora—nonpathogenic microorganisms such as bacteria and some fungi unique to skin and mucus membranes Innate Immunity: Second Line of Defense  Inflammation—programmed response to damage to the body through a response that initiates an interactive system of humoral (soluble in the blood) & cellular systems.  First response to injury that occurs within seconds after damage occurs in tissues with a blood supply  Depends on activity of cellular and chemical components  Nonspecific in that it takes place in the same way regardless of stimulus and whether exposure to the same stimulus has occurred in the past Inflammatory Process  Vasodilation slows velocity and increases blood flow to injured site  Increase vascular permeability with leakage of fluid (exudate) out of a vessel causing swelling at site  As plasma fluid moves outward, blood in the microcirculation becomes more viscous and slow flow  Increased concentration of RBCs causes localized erythema and warmth  WBCs migrate through junctions between endothelial cells lining the vessels Inflammation  Goals: o Limit and control the inflammatory process o Prevent and limit infection and further damage o Initiate adaptive immune response o Initiate healing Mast Cells  Most important cellular activator inflammatory response  Filled with granules and are located in loose connective tissue close to blood vessels in skin, GI & respiratory tracts  Release potent inducers of inflammation by the process of degranulation that dumps the content of the mast cell into bloodstream within seconds and exert effect immediately Mast Cell Degranulation  Histamine o Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the post­capillary venules o Retraction of endothelial cells lining the capillaries o Receptors  H1 receptor (pro­inflammatory)  H2 receptor (anti­inflammatory) Classic Symptoms of Acute Inflammation  Redness (erythema), heat, swelling, pain, and loss of function  Microscopic changes in microcirculation (arterioles, capillaries, & venules) near the site of injury Complement System  Consists of a large number of proteins called complement factors that make up about 10% of the total circulating protein  Activation of system produces factors that can destroy pathogens directly or can activate/ increase the activity of other cells of the inflammatory and immune response  Factors produced during activation of the complement system are among the most potent defense against bacterial infection Complement System/ Activation of C3 & C5  Opsonins (C3b) coat the surface of bacteria and increase their susceptibility to being phagocytized & killed by neutrophils & macrophages  Chemotactic factors (C5a) diffuse from inflammatory site & attract phagocytic cells to that site  Anaphylatoxin (C3a, C5a) induces rapid degranulation of mast cells that release histamine inducing vasodilation and increased capillary permeability which is a major component of inflammation  Membrane attack complex (MAC) from C5b – C9 results in a complex that creates pores in outer membranes of bacterial cells that allow water to enter causing the cell to burst/die or at least prevent its reproduction Three Major Pathways for Complement Activation  Classical—primarily activated by antibodies which are proteins of the acquired immune system  Antibodies must first bind to their targets/antigens that are molecules that stimulate production of antibodies  Antibodies activate C1 which then lead to activation of C3 and C5  Antibodies of the acquired immune response use the complement system to kill bacteria and activate inflammation Coagulation/ Clotting System  Coagulation system o Forms a fibrinous meshwork at an injured or inflamed site  Prevents the spread of infection  Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity  Forms a clot that stops bleeding  Provides a framework for repair and healing o Man substance is an insoluble protein called fibrin Coagulation System (extrinsic)  Group of plasma proteins, that when activated sequentially, form a blood clot  Tissue factor (extrinsic) pathway activates when there is tissue damage and TF is released from damaged endothelial cells in blood vessels and reacts with factor VII  Contact activation (intrinsic) pathway activates when there is an abnormal vessel wall & Factor XII is activated by contact with sub­endothelial substances Clotting System (Con’t)  Activation of Factor X begins a common pathway leading to activation of fibrin which is framework for clot formation Kinin System  Acts at site of injury to induce vasodilation and smooth muscle contraction, vascular permeability  Functions to activate, attract (chemotaxis), & assist inflammatory cells such as leukocytes  Primary kinin is bradkinin which acts with prostaglandins to produce PAIN Cytokines  Small proteins released by cells that have a specific effect on the interactions between cells, on communication between cells, or on the behavior of cells  Cytokines include the interleukins, lymphokines and cell signal molecules, such as tumor necrosis factor and the interferons, which trigger inflammation and respond to infections  Interleukins (IL) o Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation o Many types/selected examples:  IL­1 is a pro­inflammatory cytokine – produced primarily by macrophages, enhances innate & acquired immunity, & acts as a growth factor for many cells; causes fever which helps to kill off infections  IL­10 is an anti­inflammatory cytokine – produced primarily by lymphocytes, suppresses lymphocyte growth & production of pro­ inflammatory cytokines leading to down­regulation of both inflammatory & acquired immune responses  Interferon (IFN) o Protects against viral infections o Produced and released by virally infected host cells in response to viral double­ stranded RNA o Types:  IFN­alpha and IFN­beta—induce production of antiviral proteins  IFN­gamma—increases microbiocidal activity of macrophages  Tumor necrosis factor­alpha (TNF­a) o Secrete by macrophages in response to receptor recognition  Induces fever by acting as an endogenous pyrogen  Increases synthesis of inflammatory serum proteins  Causes muscle wasting (cachexia) and intravascular thrombosis  Very high levels of TNF­a can be lethal and are probably responsible for fatalities from shock caused by gram negative bacterial infections  Chemokines o Attract leukocytes to site of inflammation o Synthesized by many cells (macrophages, fibroblasts, endothelial cells) Endothelium  Endothelial cells adhere to underlying connective tissue matrix o Interact with circulating cells, platelets, plasma proteins o Regulate circulating inflammatory components o Damage to endothelial cells initiates platelet adherence due to exposure of the underlying connective tissue which is pro­thrombogenic &initiates clot formation through the intrinsic clotting pathway Platelets  Circulate in bloodstream until vascular injury occurs  Activated by tissue destruction and inflammation  Activation leads to interaction with coagulation cascade o Degranulation activity with serotonin release (acts like histamine) Phagocytes  Neutrophils o Also referred to as polymopphonuclear neutrophils (PMNs) o Predominate in early inflammatory responses o Ingest bacteria, dead cells, and cellular debris o Cells are short lived and become a component of the purulent exudate  Monocytes and macrophages o Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages o Macrophages typically arrive at the inflammatory site 24 hours or later after neutrophils  Eosinophils o Mildly phagocytic o Defense against parasites and regulation of vascular mediators  Dendritic cells o In peripheral organs and skin o Migrate through lymph vessels to lymph tissue and interact with T lymphocytes to generate an acquired immune response  T lymphocytes o Active during wound healing Phagocytosis  Process by which a cell ingests and disposes of foreign material  Production of adhesion molecules  Margination (pavementing)—leukocytes “fall out of blood flow in the middle of the vessel & stick/adhere to the endothelial cells  Diapedesis—movement of leukocytes out of circulatory system through the endothelial junctions to the site of injury Acute Inflammation  Acute o Self limiting o Local manifestations—result from vascular changes and corresponding leakge of circulating components into the tissue  Heat, swelling, redness, pain  Edudative fluids Exudative Fluids  Serous exudate o Wastery exudate: indicated early inflammation  Fibrinous exudate: thick, clotted exudate: indicates more advanced inflammation  Purulent exudate (suppurative) o Pus: indicates a bacterial infection  Hemorrhagic exudate o Exudate contains blood: indicates bleeding o Serosanguious—thin, clear, pinkish o Sanguinous—bloody Systemic Manifestations of Acute Inflammation  Fever­ caused by exogenous and endogenous pyrogens and act directly on the hypothalamus  Leukocytosis—increased number of circulating leukocytes  Increased plasma protein synthesis/ acute­phase reactants: o C­reactive protein o Fibrinogen o Haptoglobin o Amyloid Chronic Inflammation  Inflammation lasting two weeks or longer  Often related to an unsuccessful acute inflammatory response  Other causes of chronic inflammation: o High lipid and wax content of a microorganism o Ability to survive inside of the macrophage o Toxins o Chemicals, particulate matter, or physical irritants Wound Healing  Primary intention—wounds that heal under conditions of minimal tissue loss  Secondary intention—wounds that require a great deal more tissue replacement/ open wound  Dysfunctional wound healing—dysfunction during inflammatory response Dysfunction during Reconstruction Phase  Impaired collagen matrix assembly o Keloid scar – raised scar that extends beyond the original boundaries of the wound, invades surrounding tissue, & may recur after surgical removal o Hypertrophic scar – raised, but remains within original boundaries of the wound & tends to regress over time  Impaired epithelialization o Anti­inflammatory steroids, hypoxemia, and nutritional deficiencies  Wound disruption o Dehiscence (increases risk of infection) – wound pulls apart at suture line o Evisceration ­ extrusion of viscera outside the body, especially through a surgical incision.  Impaired contraction – contracture ­ a condition of shortening and hardening of muscles, tendons, or other tissue, often leading to deformity and rigidity of joints Older Adults  Impaired function of innate immune cells (phagocytes)  Impaired inflammation is likely a result of chronic illness – diabetes, CV disease, COPD  Chronic medication intake decreases the inflammatory response  Healing response is diminished because of skin’s loss of regenerative ability  Infections and chronic inflammation are more common in older adults