1. Essential to the survival of organisms is their ability to get rid of damaged or necrotic tissues and foreign invaders, such as microbes. The host response that accomplishes these goals is called inflammation. It is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes.

2. The bodys principal defenders include: plasma proteins and circulating leukocytes (white blood cells), as well as tissue phagocytes that are derived from circulating cells The presence of proteins and leukocytes in the blood gives them the ability to home to any site where they may be needed 3. Because invaders such as microbes and necrotic cells are typically present in tissues, outside the circulation, it follows that the circulating cells and proteins have to be rapidly recruited to these extravascular sites. The inflammatory response coordinates the reactions of vessels, leukocytes, and plasma proteins to achieve this goal. 4. Microbes, necrotic cells (whatever the cause of cell death) and even hypoxia can trigger the elaboration of inflammatory mediators, and thus elicit inflammation Such mediators initiate and amplify the inflammatory response and determine its pattern, severity, and clinical and pathologic manifestations 5. Inflammation may be acute or chronic, depending on the nature of the stimulus and the effectiveness of the initial reaction in eliminating the stimulus or the damaged tissues. Acute inflammation is rapid in onset (typically minutes) and is of short duration, lasting for hours or a few days 6. exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes). 7. Chronic inflammation may follow acute inflammation or be insidious in onset. It is of longer duration and is associated with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis, and tissue destruction. 8. Inflammation is terminated when the offending agent is eliminated. The reaction resolves rapidly, because the mediators are broken down and dissipated and the leukocytes have short life spans in tissues. In addition, anti-inflammatory mechanisms are activated that serve to control the response and prevent it from causing excessive damage to the host. 9. The inflammatory response is closely intertwined with the process of repair. At the same time as inflammation destroys, dilutes, and walls off the injurious agent, it sets into motion a series of events that try to heal the damaged tissue. Repair begins during inflammation but reaches completion usually after the injurious influence has been neutralized. 10. In the process of repair the injured tissue is replaced through regeneration of native parenchymal cells, by filling of the defect with fibrous tissue (scarring) or, most commonly, by a combination of these two processes 11. Inflammation may be harmful in some situations. Mechanisms designed to destroy foreign invaders and necrotic tissues have an intrinsic ability to injure normal tissues. When inflammation is inappropriately directed against self tissues or is not adequately controlled, it becomes the cause of injury and disease 12. In fact, in clinical medicine, great attention is given to the damaging consequences of inflammation. Inflammatory reactions underlie common chronic diseases, such as rheumatoid arthritis, atherosclerosis, and lung fibrosis, as well as life- threatening hypersensitivity reactions to insect bites, drugs, and toxins. 13. For this reason our pharmacies abound with anti-inflammatory drugs, which ideally would control the harmful sequelae of inflammation yet not interfere with its beneficial effects. 14. Inflammation may contribute to a variety of diseases that are not thought to be primarily due to abnormal host responses. For instance, chronic inflammation may play a role in atherosclerosis, type 2 diabetes, degenerative disorders like Alzheimer disease, and cancer. 15. Although clinical features of inflammation were described in an Egyptian papyrus dated around 3000 BC Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain). 16. A fifth clinical sign, loss of function (functio laesa), was added by Rudolf Virchow in the 19th century. In 1793 the Scottish surgeon John Hunter noted what is now considered an obvious fact: that inflammation is not a disease but a nonspecific response that has a salutary effect on its host. 17. In the 1880s the Russian biologist Elie Metchnikoff discovered the process of phagocytosis by observing the ingestion of rose thorns by amebocytes of starfish larvae and of bacteria by mammalian leukocytes. He concluded that the purpose of inflammation was to bring phagocytic cells to the injured area to engulf invading bacteria. This concept was elegantly satirized by George Bernard Shaw in his play The Doctor's Dilemma, in which one physician's cure-all is to stimulate the phagocytes 18. Sir Thomas Lewis, studying the inflammatory response in skin, established the concept that chemical substances, such as histamine (produced locally in response to injury), mediate the vascular changes of inflammation. This fundamental concept underlies the important discoveries of chemical mediators of inflammation and the use of anti-inflammatory drugs in clinical medicine. 19. Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow, (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent 20. Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation. Tissue necrosis from any cause, including ischemia (as in a myocardial infarct), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals). 21. Foreign bodies (splinters, dirt, sutures) typically elicit inflammation because they cause traumatic tissue injury or carry microbes. Immune reactions (also called hypersensitivity reactions) are reactions in which the normally protective immune system damages the individual's own tissues 22. In inflammation, blood vessels undergo a series of changes that are designed to maximize the movement of plasma proteins and circulating cells out of the circulation and into the site of infection or injury 23. The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation An exudate is an extravascular fluid that has a high protein concentration, contains cellular debris, and has a high specific gravity. Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction 24. Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes. 25. In contrast, a transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability 26. Changes in vascular flow and caliber begin early after injury and consist of the following: Vasodilation is one of the earliest manifestations of acute inflammation; sometimes it follows a transient constriction of arterioles, lasting a few seconds involves the arterioles and then leads to opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness 27. Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues 28. The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood. These changes result in dilation of small vessels that are packed with slowly moving red cells, a condition termed stasis, which is seen as vascular congestion (producing localized redness) upon examination of the involved tissue. 29. As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue 30. A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability 31. Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage Short lived 15- 30 min Although in some forms may exist after a delay of 2-12 hours (e.g. after burns, x- irradiation or ultraviolet radiation, and exposure to certain bacterial toxins Late-appearing sunburn is a good example of this type of leakage. 32. Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells 33. called transcytosis This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions. 34. The responses of leukocytes consist of two sequential sets of events: (1) recognition of the offending agents, which deliver signals that (2) activate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction. 35. Phagocytosis involves three sequential steps : (1) recognition and attachment of the particle to be ingested by the leukocyte; (2) its engulfment, with subsequent formation of a phagocytic vacuole; and (3) killing or degradation of the ingested material. 36. It is predictable that such a powerful system of host defense, with its inherent capacity to cause tissue damage, needs tight controls to minimize the damage In addition, as inflammation develops the process also triggers a variety of stop signals that serve to actively terminate the reaction 37. all acute inflammatory reactions may have one of three outcomes Complete resolution. In a perfect world, all inflammatory reactions, once they have succeeded in neutralizing and eliminating the injurious stimulus, should end with restoration of the site of acute inflammation to normal. 38. Healing by connective tissue replacement (fibrosis). Progression of the response to chronic inflammation 39. The morphologic hallmarks of all acute inflammatory reactions are dilation of small blood vessels, slowing of blood flow, and accumulation of leukocytes and fluid in the extravascular tissue 40. Serous inflammation is marked by the outpouring of a thin fluid that may be derived from the plasma or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. Accumulation of fluid in these cavities is called an effusion. The skin blister resulting from a burn or viral infection represents a large accumulation of serous fluid, either within or immediately beneath the epidermis of the skin 41. With greater increase in vascular permeability, large molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited in the extracellular space. 42. FIGURE 2-19 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface 43. This type of inflammation is characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, liquefactive necrosis, and edema fluid. Certain bacteria (e.g., staphylococci) produce this localized suppuration and are therefore referred to as pyogenic (pus-producing) bacteria 44. Purulent inflammation. A, Multiple bacterial abscesses in the lung, in a case of bronchopneumonia. B, The abscess contains neutrophils and cellular debris, and is surrounded by congested blood vessels 45. An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue 46. The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low- power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base. 47. Chronic inflammation is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations 48. Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria, and certain viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity 49. Immune-mediated inflammatory diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions immune reactions develop against the individual's own tissues, leading to autoimmune diseases 50. Prolonged exposure to potentially toxic agents, either exogenous or endogenous An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis 51. Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells Tissue destruction, induced by the persistent offending agent or by the inflammatory cells Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis 52. FIGURE 2-22 A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested. 53. Lymphocytes Plasma cells Eosinophils Mast cells 54. Granulomatous inflammation is a distinctive pattern of chronic inflammation that is encountered in a limited number of infectious and some noninfectious conditions 55. Anyone who has suffered a severe sore throat or a respiratory infection has experienced the systemic manifestations of acute inflammation. The systemic changes associated with acute inflammation are collectively called the acute-phase response, or the systemic inflammatory response syndrome. 56. Fever, characterized by an elevation of body temperature, usually by 1 to 4C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is associated with infection produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus. 57. Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli. 58. Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections Neutrophilia increase in the blood neutrophil count Lymphocytosis increase in lymphocyte Leukopenia associated with a decreased number of circulating white 59. increased pulse and blood pressure; decreased sweating, mainly because of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; rigors (shivering), chills, anorexia, somnolence, and malaise, probably because of the actions of cytokines on brain cells. 60. In severe bacterial infections (sepsis) the large amounts of organisms and LPS in the blood stimulate the production of enormous quantities of several cytokines