Porth's Essentials of Pathophysiology, 4e

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Inflammation, the Inflammatory Response, and Fever

C h a p t e r 3

cytokines and growth factors that favor tumor develop- ment and growth (see Chapter 7). 23 Among the cancers associated with chronic infection and inflammation are cervical cancer (human papillomavirus [HPV]), cancer of the liver (hepatitis B and C), cancer of the stomach ( Helicobacter pylori ), and cancer of the gallbladder (chronic cholecystitis and cholelithiasis). Causes of Chronic Inflammation Agents that evoke chronic inflammation typically are low-grade, persistent infections or irritants that are unable to penetrate deeply or spread rapidly. 1,2 Among the causes of chronic inflammation are foreign agents such as talc, silica, asbestos, and surgical suture mate- rials. Many viruses provoke chronic inflammatory responses, as do certain bacteria, such as the tubercle bacillus and the actinomyces, as well as fungi, and larger parasites of moderate to low virulence. The presence of injured tissue such as that surrounding a healing frac- ture also may incite chronic inflammation. Diseases that cause excessive and inappropriate activation of the immune system are increasingly being recognized as causes of chronic inflammation. Under certain condi- tions, immune reactions may develop against the per- son’s own tissues, leading to autoimmune disease. Obesity is a newly suspected cause of chronic inflam- mation. 24–26 During the last decade, white adipose tis- sue was recognized to be an active endocrine organ and a source of a number of proinflammatory mediators. Many of the mediators appear to play an important role in the pathogenesis of obesity-related diseases includ- ing accelerated atherosclerosis and diabetes mellitus. The link between obesity and inflammation dates back to the discovery that adipose tissue was a source of the proinflammatory cytokine TNF- α , and that adipose tis- sue TNF- α concentrations are correlated with insulin resistance both in persons with and without type 2 dia- betes mellitus. It was later found that obesity is related not only to increased number and size of adipocytes, but also to infiltration of adipose tissue by macrophages that possess the ability to produce TNF- α , nitric oxide, and other inflammatory mediators. The mechanisms mediating the proinflammatory state associated with obesity are still unclear, but recent studies suggest that circulating free fatty acids may play a role. Granulomatous Inflammation A granulomatous lesion is a distinctive form of chronic inflammation. 1,2 A granuloma typically is a small, 1- to 2-mm lesion in which there is a massing of macro- phages surrounded by lymphocytes. The macrophages are modified and, because they resemble epithelial cells, sometimes are called epithelioid cells. Like other mac- rophages, these epithelioid cells are derived originally from blood monocytes. Granulomatous inflammation is associated with foreign bodies such as splinters, sutures, silica, and asbestos and with microorganisms that cause tuberculosis, syphilis, sarcoidosis, deep fungal

Chronic Inflammation In contrast to acute inflammation, which is usually self- limited and of short duration, chronic inflammation is self-perpetuating and may last for weeks, months, or even years. 1,2,23 It may develop as a result of a recurrent or progressive acute inflammatory process or from low- grade, smoldering responses that fail to evoke an acute response. Instead of the vascular permeability changes, edema, and predominantly neutrophilic infiltration seen in acute inflammation, chronic inflammation is charac- terized by infiltration with mononuclear cells (macro- phages, lymphocytes, and plasma cells) and attempted connective tissue repair involving angiogenesis and fibrosis. Although it may follow acute inflammation, chronic inflammation often begins insidiously as a low- grade, smoldering, and asymptomatic process. This type of process is the cause of tissue damage in some of the most common disabling diseases such as atherosclerosis, chronic lung disease, rheumatoid arthritis, and inflam- matory bowel disease. There is also evidence that recurrent and persistent inflammation induces, promotes, and/or influences sus- ceptibility to cancer by causing deoxyribonucleic acid (DNA) damage, inciting tissue reparative proliferation, and/or creating an environment that is enriched with permeability), the influx of inflammatory cells such as neutrophils, and, in some cases, the widespread effects of inflammatory mediators, which produce fever and other systemic signs and symptoms. ■■ Chemical mediators are integral to initiation, amplification, and termination of inflammatory processes.The plasma is the source of mediators derived from three major protein cascades that are activated during inflammation.These protein cascades include the kallikrein-kininogen system, the coagulation system, and the complement system. Cell-derived mediators, including histamine, bradykinin, the arachididonic metabolites, platelet activating factor (PAF), and many others are released from cells at the site of inflammation. ■■ Acute inflammation may involve the production of exudates containing serous fluid (serous exudate), red blood cells (hemorrhagic exudate), fibrinogen (fibrinous exudate), or tissue debris and white blood cell breakdown products (purulent exudate). ■■ The outcome of acute inflammation generally results in one of three processes: resolution, progression to chronic inflammation, or substantial scarring and fibrosis.