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Chapter 17 Inflammation: Understanding Its Role In Acute And Chronic Disease History • Inflammation has been recognized as a component of the body’s response to injury from the time of the Egyptians • Celsus of Rome documented the four cardinal signs of inflammation. • It became clear that inflammation is an integral part of a person’s innate immunity: mechanism of nonspecific first response to pathogens, toxins, pollutants, and inhalants. • Evidence showed that chronic inflammation exists and that it can play a significant role in cardiovascular disease and Alzheimer’s Dementia (among others). • Inflammation is also a component in injuries from environmental hazards. What is Inflammation? • It is the body’s local vascular and cellular response to injury caused by factors that invade and injure the body from the outside (exogenous factors) or factors within the body (endogenous factors) that result in cellular or tissue injury. • It is part of an innate immune response: requires no previous exposure to the insult. • Response is rapid Acute Inflammation • • • • Short-term (hours or days). Abrupt in onset. Nonspecific response. 5 main symptoms: 1. 2. 3. 4. 5. Warmth Redness in area of injury Pain (throbbing) Localized swelling Loss of function in the site of injury Vascular Response • Clinical signs of acute inflammation are due to an initial vascular response localized to the area of injury • The increased blood flow and dilation of vessels (increased permeability) is caused by relaxation of vascular smooth muscle. • Stimulation is immediate in response to direct injury or IgE-mediated effects on tissue mast cells - cause cells to release Histamine. • Histamine is the predominate stimulus to vascular response, but there are also other mediators that come from plasma. Cellular Response - Neutrophils • Neutrophils are the first line of defense against foreign invaders. • Predominant cell type in normal circulation. • They are uniquely adapted to their task due to their structure. • Have a short life - replaced rapidly from bone marrow. • Arrive to site of injury quickly - become maximal within 24 - 48 hours; however, the secondary damage to tissue can also be significant. • The second phase of acute inflammatory response is marked by the accumulation of a cellular exudate of neutrophils within the area of injury. • Neutrophils engage in phagocytosis (engulf matter to prevent further harm). Phagocytosis • Matter is engulfed within a vacuole, which then fuses with a lysosome to form phagolysosome. Bacteria is then killed by lysosomal and protease enzymes. • Opsonins: factors that coat particulate matter to enhance phagocytosis. - i.e. matter is associated with ligands that can bind to receptors on the surface of neutrophils. • Phagocytosis can occur in anaerobic environment, however, the microbicidal activity of neutrophils is much greater in presence of oxygen. Cellular Response - Monocytes & Macrophages • • • • Monocytes - in circulation. Macrophages - in tissue. Are phagocytic (ameboid motion). Contain the same receptors for Toll-ligands and opsonins that are expressed on neutrophils. - Toll-like receptors bind common antigens, such as LPS in walls of gram negative bacteria. - Binding activate leukocytes and stimulates release of proinflammatory cytokines. Cellular Response - Monocytes & Macrophages • Macrophages: - Have longer life (1 or more months) - Antimicrobial metabolism produces oxygen and free radicals (nitric oxide). - Process foreign material for “presentation” to lymphocytes. • Monocytes: - circulate in blood and differentiate into macrophages in the tissue. - 2nd wave of cells at sites of injury in acute inflammation. Migration of Neutrophils and Monocytes • Migrate out of blood and into injured tissue by margination, adherence, and emigration. • Early mediators cause neutrophils, monocytes, and endothelial cells to synthesize selectins (expressed on cell surfaces). • Selectins cause contact between cells in blood and surface of endothelial cells. • Prolonged contact stimulates synthesis and expression of integrins (bind and anchor neutrophils & monocytes to venule). • Anchored cells become exposed and bound to chemoattractants (mediators) - causes cells to move into tissue. • Major chemo-attractants included C5a component, Leukotriene B4, and chemokines. Exudate • Suppurative (pus) • It is the accumulation of protein-rich fluid exudate (neutrophils and necrotic tissue). • Recognized hallmark of infection. Other exudates are named by their major component: - Serous (edema fluid) - Fibrinous (fibrin) - Hemorrhagic (blood) Manifestation and Complications of Acute Inflammation • Danger of acute inflammation: damaging tissue so that function is lost or that associated infection can extend beyond the localized area of injury to the rest of the body. • Two distinctive manifestations include formation of abscesses or ulcers. Abscesses and Ulcers • Abscess: - Compartmentalized collection of suppurative exudate and tissue necrosis enclosed by tissue. - Hard to heal - inner core is dead tissue (no vascular supply). - Risk: on-going tissue injury and widespread infection (sepsis). • Ulcer: - localized site of inflammation and necrosis at the surface of skin or the inner surface of an organ. - Sufficient damage causes gap/hole in tissue surface. - Non-removed infectious agents can penetrate deeper into tissue and cause systemic infection. Systemic Signs of Inflammation • Leukocytosis: - Increase in circulating leukocytes. - Occurs within hours of stimulus. - Mobilized from bone marrow. - Granulopoiesis: process when bone marrow generates new cells in proportion to demand. • Fever: - Results from stimulation of the hypothalmic thermoregulatory center by cytokines released from activated macrophages and other cells. Healing and Repair Three overlapping phases (mediated by cytokines): 1. Influx of macrophages and clearance of debris. 2. Influx and regeneration of endothelial cells and new vessel formation (angiogenesis). - Dehiscence: time when regenerating tissue is least strong and most in danger of tearing open. 3. Proliferation of fibroblasts and myofibroblasts that produce a progressive accumulation of collagen, as required by the extent of the wound. - Collagen and scar hold tissue together against forces that might pull it apart. Healing and Repair - Cont’d • When granulation tissue is present, which is the loose matrix of regenerating connective tissue, the wound is “organizing” or “organized.” • Wounds are healed by “first” or “second” intention: -First: the edges of the wound can be brought together, usually by stitches (little tissue regeneration). -Second: a wound that is so large that the edges cannot be approximated, scar formation is the inevitable result. • Healing without loss of function or scar requires that the tissue remains intact, so that regenerating cells can be oriented in a way that allows them to function properly. Causes for Delay or Absence of Healing • Host factors that prevent the regeneration or function of native and new connective tissue cells. • Large injury area. • Stimulus for inflammation cannot be removed. • Inadequate blood supply (diabetes). • Malnutrition (insufficient protein) • Suppression of the immune response. • Vitamin C deficiency (inadequate collagen synthesis). Chronic Inflammation • Occurs when inciting stimuli (chronic infections, tissue irritants, or altered proteins) for inflammation cannot be removed from the body. • Prolonged activation of the inflammatory response. • Lymphocytes and macrophages predominate. • Macrophage chemo-attractant production favors migration of lymphocytes to injury area, rather than neutrophils (acute). • Ongoing tissue injury incites an ongoing effort to heal - causes a progressive increase in the accumulation of collagen and scar formation in the tissue. Chronic Inflammation - Cont’d • Associated with many major chronic organ system diseases. • The progressive loss of functional tissue and the increase of scar tissue in the organ impact on the function of the organ and ultimately results in its failure. • Examples include: - Chronic Hepatitis caused by Hepatitis C virus infecting the liver; can lead to Cirrhosis. Hepatitis C virus also causes portal hypertension and hepatocellular carcinoma. - Atherosclerosis. - Chronic Bronchitis. - Collagen vascular disease (rheumatoid arthritis). - Inflammatory bowel disease. Evidence of Chronic Inflammation • • • • • Tissue injury and scar. An infiltrate of lymphocytes. Lesser numbers of macrophages. Occasional antibody-producing plasma cells. Granuloma: - A distinctive inflammatory infiltrate that contains an aggregate of macrophages surrounded by lymphocytes. - When activated by lymphocyte cytokines, the macrophages become “epithelioid.” - Form when macrophages cannot kill certain organisms or degrade certain proteins that are resistant to them. Causes of Chronic Inflammation Associated with Granulomas • Mycobacterium tuberculosis - Caseous necrosis - Latent Mycobacteria can become reactivated in conditions of immunosupression. • • • • Sarcoidosis Fungal infections Parasitic infections Inorganic substances Inflammation and the Shifting Burden of Disease • Infectious diseases accounted for the majority of Disability Adjusted Life Years (DALYS) before modern medicine. • Progression in medicine and living conditions increased lifespan, but also increased the rates of chronic diseases. • Currently, chronic disease is the major source of DALYS. • It’s important to understand the risk factors, disease mechanisms, and health consequences of chronic conditions. • Inflammation is an example of an evolutionary adaptive response that has become maladaptive in today’s environment. • Chronic inflammation is quiet injurious and contributes to many chronic conditions (heart attack, Alzheimer’s, cancer).