Inflammatory And Allergic Responses

The proinflammatory actions of PAF and its elaboration by endothelial cells, leukocytes, and mast cells under inflammatory conditions are well characterized. PAF and PAF-like molecules are thought to contribute to the pathophysiology of inflammatory disorders, including anaphylaxis, bronchial asthma, endotoxic shock, and skin diseases. The plasma concentration of PAF is increased in experimental anaphylactic shock, and the administration of PAF reproduces many of its signs and symptoms, suggesting a role for the autacoid in anaphylactic shock. In addition, mice over expressing the PAF receptor exhibit bronchial hyperreactivity and increased lethality when treated with endotoxin. PAF receptor knockout mice display milder anaphylactic responses to exogenous antigen challenge, including less cardiac instability, airway constriction, and alveolar edema; they are, however, still susceptible to endotoxic shock. Deletion of the PAF receptor augments the lethality of infection with gram-negative bacteria while improving host defense against gram-positive pneumococcal pneumonia.

Despite the broad implications of these observations, the effects of PAF antagonists in the treatment of inflammatory and allergic disorders have been disappointing. Although PAF antagonists reverse the bronchoconstriction of anaphylactic shock and improve survival in animal models, the impact of these agents on animal models of asthma and inflammation is marginal. Similarly, in patients with asthma, PAF antagonists partially inhibit the bronchoconstriction induced by antigen challenge but not by challenges by methacholine, exercise, or inhalation of cold air. These results may reflect the complexity of these pathological conditions and the likelihood that other mediators contribute to the inflammation associated with these disorders.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at


INFLAMMATION The inflammatory process is the response to an injurious stimulus evoked by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries). The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences.

Inflammatory responses occur in three distinct temporal phases, each apparently mediated by different mechanisms: (1) an acute phase characterized by transient local vasodilation and increased capillary permeability; (2) a delayed, subacute phase characterized by infiltration of leukocytes and phagocytic cells; and (3) a chronic proliferative phase, in which tissue degeneration and fibrosis occur.

Many mechanisms are involved in the promotion and resolution of the inflammatory process. Recent work has focused on adhesive interactions, including the E-, P-, and L-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and leukocyte integrins, in the adhesion of leukocytes and platelets to endothelium at sites of inflammation.

Activated endothelial cells play a key role in "targeting" circulating cells to inflammatory sites. Cell adhesion occurs by recognition of cell-surface glycoproteins and carbohydrates on circulating cells due to the augmented expression of adhesion molecules on resident cells. Thus, endothelial activation results in leukocyte adhesion as the leukocytes recognize newly expressed L-selectin and P-selectin. Some, but not all, traditional non-steroidal anti-inflammatory drugs (tNSAIDs) may interfere with adhesion by inhibiting expression or activity of certain of these cell-adhesion molecules.

Recruitment of inflammatory cells to sites of injury involves the concerted interactions of several types of soluble mediators. These include the complement factor C5a, platelet-activating factor, and the eicosanoid LTB4 (see Chapter 25). All can act as chemotactic agonists. Several cytokines also play essential roles in orchestrating the inflammatory process, especially interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a). IL-1 and TNF are considered principal mediators of the biological responses to bacterial lipopolysaccharide (LPS, also called endotoxin). They are secreted by monocytes and macrophages, adipocytes, and other cells. Working in concert with each other and various cytokines and growth factors (including IL-8 and granulocyte-macrophage colony-stimulating factor; see Chapter 53), they induce gene expression and protein synthesis in a variety of cells to mediate and promote inflammation.

Intradermal, intravenous, or intra-arterial injections of small amounts of prostaglandins mimic many components of inflammation. Administration of prostaglandin E2 (PGE2) or prostacyclin (PGI2) causes erythema and an increase in local blood flow. Such effects may persist for up to 10 hours with PGE2 and include the capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin II, properties not generally shared by other inflammatory mediators. In contrast to their long-lasting effects on cutaneous vessels and superficial veins, prostaglandin-induced vasodilation in other vascular beds vanishes within a few minutes.

Although PGE1 and PGE2 (but not PGF2a) cause edema, it is not clear if they can increase vascular permeability in the postcapillary and collecting venules without the participation of other inflammatory mediators (e.g., bradykinin, histamine, and leukotriene C4 [LTC4]). Furthermore, PGE1 is not produced in significant quantities except under rare circumstances such as essential fatty acid deficiency. Unlike LTs, prostaglandins are unlikely to be involved in chemotactic responses, even though they may promote the migration of leukocytes into an inflamed area by increasing blood flow.

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