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Chapter: Basic & Clinical Pharmacology : Nitric Oxide

Infection & Inflammation - Nitric Oxide in Disease

The generation of NO has both beneficial and detrimental roles in the host immune response and in inflammation.

INFECTION & INFLAMMATION

The generation of NO has both beneficial and detrimental roles in the host immune response and in inflammation. The host response to infection or injury involves the recruitment of leuko-cytes and the release of inflammatory mediators, such as tumor necrosis factor and interleukin-1. 

This leads to induction of iNOS in leukocytes, fibroblasts, and other cell types. The NO that is produced, along with peroxynitrite that forms from its interaction with superoxide, is an important microbicide. NO also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, TH1 cells  respond by synthesizing NO, which has roles in TH1 cells. The importance of NO in TH1 cell function is demonstrated by the impaired protective response to injected parasites in animal models after inhibition of iNOS. NO also stimulates the synthesis of inflammatory prostaglandins by activating cyclooxygenase isoenzyme 2 (COX-2). Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation.

However, in both acute and chronic inflammatory condi-tions, prolonged or excessive NO production may exacerbate tissue injury. Indeed, psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demon-strate elevated levels of NO and iNOS, suggesting that persistent iNOS induction may contribute to disease pathogenesis. Moreover, these tissues also exhibit increased levels of nitroty-rosine, indicating excessive formation of peroxynitrite. In several animal models of arthritis, increasing NO production by dietary L-arginine supplementation exacerbates arthritis, whereas pro-tection is seen with iNOS inhibitors. Thus, inhibition of the NO pathway may have a beneficial effect on a variety of acute and chronic inflammatory diseases.


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