Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

Systemic Manifestations of Inflammation Under optimal conditions, the inflammatory response remains confined to a localized area. In some cases, however, local injury can result in prominent systemic manifestations as inflammatory mediators are released into the circulation. The most prominent systemic manifestations of inflammation include the acute-phase response, alterations in white blood cell count (leuko- cytosis or leukopenia), and fever. Localized acute and chronic inflammation may extend to the lymphatic system and lead to a reaction in the lymph nodes that drain the affected area. Painful palpable lymph nodes are more commonly associated with inflammatory pro- cesses, whereas nonpainful nodes are more characteris- tic of neoplasms. Acute-Phase Response Along with the cellular responses that occur during the inflammatory response, a constellation of systemic effects called the acute-phase response occurs. 1,2 The acute-phase response, which usually begins within hours or days of the onset of inflammation or infec- tion, includes changes in the concentrations of plasma proteins, skeletal muscle catabolism, negative nitro- gen balance, elevated erythrocyte sedimentation rate, and increased numbers of leukocytes. Other mani- festations of the acute-phase response include fever, increased heart rate, anorexia, somnolence, and malaise. Acute-Phase Proteins During the acute-phase response, the liver dramatically increases the synthesis of acute-phase proteins such as fibrinogen, C-reactive protein (CRP), and serum amy- loid A protein (SAA) that serve several different defense functions. 1,2 The synthesis of these proteins is stimulated by cytokines, especially TNF- α , IL-1 (for SAA), and IL-6 (for fibrinogen and CRP). C-reactive protein was named because it precipitated with the C fraction (C polypeptide) of pneumococci. The function of CRP is thought to be protective, in that it binds to the surface of invading microorganisms and targets them for destruction by complement and phagocytosis. Although everyone maintains a low level of CRP, this level rises when there is an acute inflammatory response. 27 Recent interest has focused on the use of high-sensitivity CRP (hsCRP) serum measurements as a marker for increased risk of myocardial infarction in persons with coronary heart dis- ease. 28,29 It is believed that inflammation involving athero- sclerotic plaques in coronary arteries may predispose to thrombosis and myocardial infarction (see Chapter 18). During the acute-phase response, SAA protein replaces apolipoprotein A, a component of high-density lipoprotein (HDL) particles (see Chapter 18). This pre- sumably increases the transfer of HDLs from liver cells to macrophages, which can then utilize these particles

infections, and brucellosis. These types of agents have one thing in common: they are poorly degraded and usually are not easily controlled by other inflammatory mechanisms. The epithelioid cells in granulomatous inflammation may clump in a mass or coalesce, forming a multinucleated giant cell (often referred to as a foreign body giant cell) that attempts to surround the foreign agent (Fig. 3-6). A dense membrane of connective tissue eventually encapsulates the lesion and isolates it. FIGURE 3-6. Foreign body giant cell.The numerous nuclei are randomly arranged in the cytoplasm. (From Rubin E, Farber LL. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams &Wilkins; 1999:40.) ■■ Chronic inflammation involves infiltration with macrophages, lymphocytes, and fibroblasts, leading to persistent inflammation, fibroblast proliferation, and scar formation. ■■ Among the conditions associated with chronic inflammation and inappropriate activation of the immune system are low-grade inflammation associated with atherosclerosis and type 2 diabetes mellitus; autoimmune disorders; and susceptibility to cancer due to deoxyribonucleic acid damage, increased tissue proliferation, and creation of an environment rich in cytokines and growth factors that favor tumor cell development and growth. ■■ A granulomatous lesion is a distinctive form of chronic inflammation characterized by aggregates of epithelioid macrophages that “wall off” the causal agent. Granulomatous inflammation is associated with foreign bodies such as splinters, sutures, silica, and asbestos and with microorganisms that cause tuberculosis, syphilis, sarcoidosis, deep fungal infections, and brucellosis. SUMMARY CONCEPTS