inflammation and repair

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  • 1. INFLAMMATION AND REPAIR Navid Jubaer Lecturer Department of Pharmacy University of Asia Pacific

2. Definition Inflammation is a non specific, localized complex immune reaction of the organism, which tries to localize the injurious agent and leading to the exudation and accumulation of protein-rich fluids and leucocytes, provided that the injury does not destroy the tissue. It consist in vascular, metabolic, cellular changes, triggered by the entering of pathogen agent in healthy tissues of the body. 3. Inflammation: Beneficial or Harmful? Inflammation is usually a protective response which is beneficial for human body. The purpose of inflammation is: To dilute, localize and destroy injurious agent To limit tissue injury To restore the tissue towards normality However, inflammation may be harmful if left untreated or the inflammation due to hypersensitivity reactions 4. Types of Inflammation Acute Inflammation: It is an immediate and rapid response of living tissue to an injurious agent and lasts for minute to few days. Histologically, there is extravascular accumulation of protein-rich fluid and leucocytes, mainly neutrophils in many acute inflammation due to exudation. It is an exudative lesion Chronic Inflammation: It is the inflammation that persists for weeks to months. Histologically, there is extravascular accumulation of lymphocytes and macrophages, tissue destruction and attempts of healing by proliferation of small blood vessels and 5. Etiology The causes of inflammation are many and varied: Exogenous causes: Physical agents Mechanical agents: fractures, foreign corps, sand, etc. Thermal agents: burns, freezing Chemical agents: toxic gases, acids, bases Biological agents: bacteria, viruses, parasites Endogenous causes: Circulation disorders: thrombosis, infarction, hemorrhage Enzymes activation e.g. acute pancreatitis Metabolic products deposals uric acid, urea Immune reactions e.g. allergic rhinitis, acute glomerulonephritis 6. Cardinal Signs Celsus described the local reaction of injury in terms that have come to be known as the cardinal signs of inflammation. These signs are: rubor (redness) tumor (swelling) calor (heat) dolor (pain) functio laesa, or loss of function (In the second century AD, the Greek physician Galen added this fifth cardinal sign) 7. Changes/Events at The Injured Site Acute inflammatory reaction and the changes it causes is stereotyped and are grouped together as following: Vascular changes a) Changes in vascular calibre and flow b) Increased vascular permeability (vascular leakage) Exudation of blood constituents a) Fluid exudate b) Cellular exudate Changes in other tissue 8. Vascular Changes At the site of injury, the changes occur in the microvasculature consisting of arterioles, venules and capillaries. The changes are Changes is the calibre of blood vessel and blood flow Structural changes that allows the plasma proteins and blood cells to leak 9. Changes in vascular calibre and flow Changes occur in the following order: Transient vasoconstriction of arterioles. It disappears within 3-5 seconds in mild injuries. In more severe injury It may last several minutes Vasodialation: It causes opening of sphincters and capillary beds at the injured site which is temporarily shut down due to injury and persists for a short time Vasodialation helps to increase the blood flow which leads to rubor (redness) and calor (heat) Slowing of blood flow or stasis due to formation of exudate and increased viscosity of blood In mild injury, it takes 15-30 minuets for these events, and with severe injury, it may occur in a few minutes 10. Increased vascular permeability (vascular leakage) A hallmark of acute inflammation (escape of a protein-rich fluid). It affects small & medium size venules, through gaps between endothelial cells 11. Mechanism of Vascular Leakage 1. Formation of endothelial gaps in venules This is the most common mechanism of vascular leakage It is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other classes of chemical mediators. It occurs rapidly after exposure to the mediator and is usually reversible and short-lived (15 to 30 minutes). It is known as immediate transient response. It affects venules (20 to 60 m in diameter), leaving capillaries and arterioles unaffected 12. 2. Direct injury (Immediate sustained reactions) Direct endothelial injury (necrosis and detachment) Direct damage to the endothelium by the injurious stimulus, as, severe burns or lytic bacterial infections. Neutrophils may also injure the endothelial cells. In most instances, leakage starts immediately after injury and is sustained at a high level for several hours until the damaged vessels are thrombosed or repaired. All levels of the microcirculation are affected: venules, capillaries, and arterioles 13. 3. Delayed prolonged leakage Relatively common type of increased permeability that begins after a delay of 2 to 12 hours, lasts for several hours or even days Involves venules as well as capillaries. Such leakage is caused by mild to moderate thermal injury, x- radiation or ultraviolet radiation, sunburn and certain bacterial toxins. The mechanism of such leakage is unclear. It may result from the direct effect of the injurious agent, leading to delayed endothelial cell damage (perhaps by apoptosis), or the effect of cytokines causing endothelial retraction. 14. 4. Leukocyte-mediated endothelial injury. Leukocytes adhere to endothelium relatively early in inflammation. Such leukocytes may be activated in the process, releasing toxic oxygen species and proteolytic enzymes, which then cause endothelial injury or detachment, resulting in increased permeability. In acute inflammation, this form of injury is largely restricted to vascular sites, such as venules and pulmonary and glomerular capillaries. 15. 5. Increased transcytosis across the endothelial cytoplasm Transcytosis occurs across channels consisting of clusters of interconnected endothelial cells This mechanism of increased permeability is induced by histamine and most chemical mediators 16. 6.Leakage from new blood vessels It occurs during angiogenesis in early healing phases that follow inflammation. 17. Exudation of Blood Constituents Exudation is the leaking of blood constituents from blood vessels into interstitial tissue. Exudate (or inflammatory edema) contains protein and leukocytes Fluid exudate Fluid exudate is formed by the plasma constituents- fluid, solute and proteins. It may have the same chemical composition as that of plasma Cellular exudate Circulating leucocytes constitute the cellular exudate. In most cases, the cells are neutrophils and monocytes Leukocyte extravasation 18. Leukocyte Extravasation It is the sequence of events of migration of leucocytes from vessel lumen to the interstitial tissue Leukocyte regulates the inflammatory reactions of cytokines and other arachidonic acid metabolites such as prostaglandins, thrombroxane A2 etc. 19. Phagocytosis Phagocytosis is the process of engulfment of particulate matters such as microbes, immune complex, cellular debris by phagocytes. Usually, neutrophils and macrophages are the phagocytes. Phagocytosis involves three distinct steps: 1. Recognition and attachment 2. Engulfment 3. Killing and degradation Figure: Phagocytosis 20. Step-1(Recognition and attachment): Neutrophils and macrophages recognize and attach microbes by several membrane receptors. Opsonization further enhances this step. Opsonin is a substance capable of enhancing phagocytosis by coating the microbes and making it more active for binding to specific receptors Step-2 (Engulfment): Pseudopods flow around the microbes and enclose it within a phagosome formed by the plasma membrane of the cell which fuses with the limiting membrane of lysosomal granule forming phagolysosome Step-3 (Killing and degradation): It is the ultimate step in the elimination of infectious agents i.e. the microbes 21. Chemical Mediators of Inflammation Changes in inflammatory responses are due to the production of chemical mediators in and around the area. These mediators performs their activity by binding to specific receptors or by some oxidative or enzymatic activity These mediators can be derived from cells or plasma 22. Chemical mediators from cells: Histamine Serotonin Lysosomal enzymes Prostaglandins Leukotrienes and lipoxins Platelet activating factors Cytokines Nitric oxide Activated oxygen species 23. Chemical mediators from plasma: Complement fragments- C3a, C5a, C3b etc Kinins- bradykinins, kallikrein Thrombin, fibrinopeptides etc Histamine It is found in high concentration in platelets, basophils, and mast cells Causes dilation and increased permeability of capillaries 24. Prostaglandins The prostaglandins are ubiquitous, lipid soluble molecules derived fro arachidonic acid, a fatty acid liberated from cell membrane phospholipids, through the cyclooxygenase pathway. Prostaglandins contribute to vasodilation, capillary permeability, and the pain and fever that accompany inflammation. The stable prostaglandins (PGE1 and PGE2) induce inflammation and potentiate the effects of histamine and other inflammatory mediators They cause the dilation of precapillary arterioles (edema), lower the blood pressure, modulates receptors activity and affect the phagocytic activity of leukocytes. The prostaglandin thromboxane A2 promotes platelet aggregation and vasoconstriction. 25. Leukotrienes The leukotrienes are formed from arachidonic acid, but through the lipoxygenase pathway. Histamine and leukotrienes are complementary in action in that they have similar functions. Histamine is produced rapidly and transiently while the more potent leukotrienes are being synthesized slo


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