Porth's Essentials of Pathophysiology, 4e

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Inflammation, the Inflammatory Response, and Fever

C h a p t e r 3

keratinocytes). The secretion of TNF- α and IL-1 can be stimulated by bacterial toxins, immune cells, injury, and a variety of inflammatory stimuli. TNF- α and IL-1 induce endothelial cells to express adhesion molecules and release other cytokines, chemokines, and reactive oxygen species. Tumor necrosis factor- α induces priming and aggregation of neutrophils, leading to augmented responses of these cells to other mediators. Interleukin-1 and TNF- α are also mediators of the acute-phase responses associated with infection or injury. Features of these systemic responses include fever, hypotension and increased heart rate, anorexia, release of neutrophils into the circulation, and increased levels of corticoste- roid hormones. Chemotactic cytokines, or chemokines , are a family of small proteins that act primarily as chemoattractants that both recruit and direct the migration of inflammatory and immune cells 20 (see Chapter 15). Chemokines gener- ate a chemotactic gradient by binding to proteoglycans on the surface of endothelial cells or in the extracellu- lar matrix. 20 As a result, high concentrations of chemo- kines persist at sites of tissue injury or infection. Two classes of chemokines have been identified: inflamma- tory chemokines and homing chemokines. Inflammatory chemokines are produced in response to bacterial toxins and inflammatory cytokines (i.e., IL-1, TNF- α ). These chemokines recruit leukocytes during an inflammatory response. Homing chemokines are constantly produced, with the genes that control their production being up-regulated during inflammatory reactions. Nitric Oxide. Nitric oxide (NO), which is produced by a variety of cells, plays multiple roles in inflammation, including relaxation of vascular smooth muscle; antag- onism of platelet adhesion, aggregation, and degranu- lation; and as regulator of leukocyte recruitment. 2 Blocking of NO production under normal conditions promotes leukocyte rolling and adhesion to postcapillary venules and delivery of exogenous NO reduces leuko- cyte recruitment. Thus, production of NO appears to be an endogenous compensatory mechanism that reduces the cellular phase of inflammation. Impaired production of NO by vascular endothelial cells is implicated in the inflammatory changes that occur with atherosclerosis (see Chapter 18). Nitric oxide and its derivatives also have antimicrobial actions, and thus NO is also a host mediator against infection. Reactive Oxygen Species. Reactive oxygen species may be released extracellularly from leukocytes after exposure to microbes, cytokines, and immune com- plexes, or in the phagocytic process that occurs dur- ing the cellular phase of the inflammatory process. The superoxide radical, hydrogen peroxide, and hydroxyl radical (discussed in Chapter 2) are the major species produced within the cell. These species can combine with NO to form other reactive nitrogen intermedi- ates. Extracellular release of low levels of these potent mediators can increase the expression of cytokines and endothelial adhesion molecules, amplifying the cascade that elicits the inflammatory process, 2 and increase cell

factor-induced platelet aggregation and degranulation at the site of injury enhances serotonin release, thereby causing changes in vascular permeability. It also enhances leukocyte adhesion, chemotaxis, and leukocyte degranu- lation and stimulates the synthesis of other inflammatory mediators, especially the prostaglandins. Cytokines and Chemokines. Cytokines are low- molecular-weight proteins that are important cellular messengers. They modulate the function of cells by paracrine and autocrine mechanisms to cause responses in neighboring cells and the cells that produced the cyto- kine, respectively. They are produced by many cell types, including activated macrophages and lymphocytes, endothelial cells, epithelial cells, and fibroblasts. 1,2,18 Although well known for their role in adaptive immune responses, these proteins also play important roles in both acute and chronic inflammation. Tumor necrosis factor- α (TNF- α ) and interleukin-1 (IL-1) are two of the major cytokines that mediate inflammation. The major cellular source of TNF- α and IL-1 is activated macrophages (Fig. 3-5). Interleukin-1 is also produced by many other cell types, including neutrophils, endothelial cells, and epithelial cells (e.g.,

Gram-negative bacteria

T cells

Macrophage

IFN- γ

LPS

TNF- α , IL-1

ENDOTHELIAL CELLS Adhesion molecules Cytokines

ACUTE-PHASE RESPONSE

NEUTROPHILS

Fever Anorexia Hypotension Increased heart rate Corticosteroid and ACTH release

Aggregation Priming

Eicosanoids Chemokines Oxygen radicals

FIGURE 3-5. Central role of interleukin (IL)-1 and tumor necrosis factor (TNF)- α in inflammation. Lipopolysaccharide (LPS) and interferon (IFN)- γ activate macrophages to release inflammatory cytokines, principally IL-1 andTNF- α , responsible for directing both local and systemic inflammatory responses. ACTH, adrenocorticotrophic hormone. (From Murphy HS. Inflammation. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012:60.)