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 leukocytes and the release of inflammatory mediators, such as tumor necrosis factor and interleukin-1. This leads to a marked increase in iNOS levels and activity 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 (see Chapter 55) 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 conditions, prolonged or excessive NO production may exacerbate tissue injury. Indeed, psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of NO and iNOS, suggesting that persistent iNOS induction may contribute to disease pathogenesis. Moreover, these tissues also exhibit increased levels of nitrotyrosine, indicating excessive formation of peroxynitrite. In several animal models of arthritis, increasing NO production by dietary l-arginine supplementation exacerbates arthritis, whereas protection 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.
NO has an important role in the central nervous system as a neurotransmitter (see Chapter 21). Unlike classic transmitters such as glutamate or dopamine, which are stored in synaptic vesicles and released in the synaptic cleft upon vesicle fusion, NO is not stored, but rather is synthesized on demand and immediately diffuses to neighboring cells. NO synthesis is induced at postsynaptic sites in neurons, most commonly upon activation of the NMDA subtype of glutamate receptor, which results in calcium influx and activation of nNOS. In several neuronal subtypes, eNOS is also present and activated by neurotransmitter pathways that lead to calcium influx. NO synthesized postsynaptically may function as a retrograde messenger and diffuse to the presynaptic terminal to enhance the efficiency of neurotransmitter release, thereby regulating synaptic plasticity, the process of synapse strengthening that underlies learning and memory. Because aberrant NMDA receptor activation and excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases, including stroke, amyotrophic lateral sclerosis, and Parkinson’s disease, therapy with NOS inhibitors may reduce neuronal damage in these conditions. However, clinical trials have not clearly supported any benefit of NOS inhibition, which may reflect nonselectivity of the inhibitors, resulting in inhibition of the beneficial effects of eNOS.