Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

proliferation. However, at higher levels these mediators can produce endothelial cell damage, with a resultant increase in vascular permeability; inactivate antiprote- ases, such as α 1 -antitrypsin, which protect against lung damage in smokers; and produce injury to other cell types, including red blood cells. 2 Thus, the influence of ROS in any inflammatory process depends on a bal- ance between the generation and inactivation of these metabolites. Local Manifestations The local manifestations of acute inflammation, which are determined by severity of the reaction, its specific cause, and the site of involvement, can range from mild swelling and redness to abscess formation or ulceration. As part of the normal defense reaction, inflammation can also injure adjacent tissues. 2 In some infections, such as tuberculosis and certain viral infections, the host response can cause more damage than the microbe itself. As a normal attempt to clear damaged and dead tissues (e.g., after a myocardial infarction), the inflammatory response may prolong and exacerbate the injurious con- sequences of the infarction. Characteristically, the acute inflammatory response involves the production of exudates. These exudates vary in terms of fluid type, plasma protein content, and presence or absence of cells. They can be serous, hemor- rhagic, fibrinous, membranous, or purulent. Often the exudate is composed of a combination of these types. Serous exudates are watery fluids low in protein con- tent that result from plasma entering the inflammatory site. Hemorrhagic exudates occur when there is severe tissue injury that causes damage to blood vessels or when there is significant leakage of red cells from the capillaries. Fibrinous exudates contain large amounts of fibrinogen and form a thick and sticky meshwork, much like the fibers of a blood clot. Membranous or pseudo- membranous exudates develop on mucous membrane surfaces and are composed of necrotic cells enmeshed in a fibropurulent exudate. A purulent or suppurative exudate contains pus, which is composed of degraded white blood cells, pro- teins, and tissue debris. The term pyogenic refers to “pus forming.” Certain pyogenic microorganisms, such as Staphylococcus , are more likely to induce localized suppurative inflammation than others. An abscess is a localized area of inflammation containing a purulent exudate. Abscesses typically have a central necrotic core containing purulent exudates surrounded by a layer of neutrophils. 2 Fibroblasts may eventually enter the area and wall off the abscess. Because antimicrobial agents cannot penetrate the abscess wall, surgical incision and drainage may be required as a cure. An ulceration refers to a site of inflammation where an epithelial surface (e.g., skin or gastrointestinal epithe- lium) has become necrotic and eroded, often with asso- ciated subepithelial inflammation. Ulceration may occur as the result of traumatic injury to the epithelial surface (e.g., peptic ulcer) or because of vascular compromise

(e.g., foot ulcers associated with diabetes). In chronic lesions where there is repeated insult, the area surrounding the ulcer develops fibroblastic proliferation, scarring, and accumulation of chronic inflammatory cells. 2 Resolution Although the manifestations of acute inflammation are largely determined by the nature and intensity of injury, the tissue affected, and the person’s ability to mount a response, the outcome generally results in one of three pro- cesses: resolution, progression to chronic inflammation, or substantial scarring and fibrosis. 2 Resolution involves the replacement of any irreversibly injured cells and return of tissues to their normal structure and function. 21,22 It is seen with short-lived and minimal injuries and involves neutralization or degradation of inflammatory mediators, normalization of vascular permeability, and cessation of leukocyte infiltration. Progression to chronic inflamma- tion may follow acute inflammation if the offending agent is not removed. Depending on the extent of injury, as well as the ability of the affected tissues to regenerate, chronic inflammation may be followed by restoration of normal structure and function. Scarring and fibrosis occurs when there is substantial tissue injury or when inflammation occurs in tissues that do not regenerate. Although the mechanisms involved in the resolution of acute inflammation have remained somewhat elusive, emerging evidence suggests that an active, coordinated program of resolution begins in the first hours after an inflammatory response begins. 2,21 Studies suggest that after entering the site of acute inflammation, neutrophils trigger a switch from the previously described proinflam- matory eicosanoids (e.g., prostaglandins and leukotri- enes) to other anti-inflammatory classes of eicosanoids, also generated from arachidonic acid. These eicosanoids initiate the termination sequence during which neutro- phil recruitment ceases and programmed cell death by apoptosis commences. The apoptotic neutrophils then undergo phagocytosis by macrophages, leading to their clearance and release of anti-inflammatory and repara- tive cytokines. Although much new information regard- ing the resolution of inflammation has been obtained over the past few years, many issues require further clar- ification. New therapeutic targets are currently being investigated and potential proresolution properties of existing drugs studied. These discoveries may bring profound advances in therapies aimed at reducing the adverse effects of persistent inflammation.

SUMMARY CONCEPTS

■■ The classic signs of an acute inflammatory response are redness, swelling, local heat, pain, and loss of function.These manifestations can be attributed to the immediate vascular changes that occur (vasodilation and increased capillary