Nitric oxide immune response

Wei, X.Q. et al., Altered immune responses in mice lacking inducible nitric oxide synthase, Nature, 375, 408, 1995. 

Inflammation is the normal host response to infection or injury that mediates immune elimination of pathogens and tissue repair. Inflammatory processes include increased production of cytokines, chemokines, nitric oxide, and eicosanoids by the innate immune system in conjunction with altered leukocyte homing, all of which greatly impact acquired immunity. Aberrant inflammatory responses evoke both acute injury such... 

Nitric oxide is important to a wide variety of mammalian physiological processes (1,2), beyond being a constituent of air pollution (3). Natural physiological activities are now known to include roles in blood pressure control, neurotransmission and immune response, and a number of disease states involving NO imbalances have been reported (2,4) as the result of extensive research activity into the chemistry, biology and pharmacology of NO. Understanding the fundamental reaction mechanisms... 

There is a great deal of evidence that AmB can exert a number of effects directly on cells of the immune system, and particularly on macrophages to increase nonspecific defense mechanisms against pathogens and cancer cells. These mechanisms include the production of nitric oxide (NO) (32) and tumor necrosis factor alpha (TNF-a) (33), which could contribute to the antifungal and antiparasitic activity of AmB. However, excess TNF-a production could also be responsible for some of the side effects associated with AmB treatment, such as fever and chills. 

Physiological sites proposed for nitric oxide action include the immune system, where nitric oxide acts as a cytostatic agent, is tumoricidal, and can inhibit viral replication. In the cardiovascular system, nitric oxide is the biological mediator of vasodilator responses to agents such as acetylcholine and bradykinin, which act as receptors on endothelial cells to activate NOS and stimulate nitric oxide production. Diffusible nitric oxide then activates guanylate cyclase in vascular smooth muscle cells, leading to the production of cyclic guano-sine monophosphate (GMP) and vasodilation. In the brain, stimulation of A-methyl-o-aspartate receptors on... 

Nitric oxide also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, THl cells (see Chapter 56 Immunopharmacology) respond by synthesizing nitric oxide. Inhibition of NOS and knockout of the NOS-2 gene can markedly impair the protective response to injected parasites in animal models. 

Irritant dermatitis does not involve an immune response and is typically caused by contact with corrosive substances that exhibit extremes of pH, oxidizing capability, dehydrating action, or tendency to dissolve skin lipids. In extreme cases of exposure, skin cells are destroyed and a permanent scar results. This condition is known as a chemical burn. Exposure to concentrated sulfuric acid, which exhibits extreme acidity, or to concentrated nitric acid, which denatures skin protein, can cause bad chemical bums. The strong oxidant action of 30% hydrogen peroxide likewise causes a chemical bum. Other chemicals causing chemical bums include ammonia, quicklime (CaO), chlorine, ethylene oxide, hydrogen halides, methyl bromide, nitrogen oxides, elemental white phosporous, phenol, alkali metal hydroxides (NaOH, KOH), and toluene diisocyanate. 

NOS is an important signaling enzyme that synthesizes L-citrulline and nitric oxide (NO) from L-arginine and O2 via two turnovers in a P450-like catalytic cycle (Scheme 2). NOS participates in physiological processes such as neurotransmission, vasodilation, and immune response [54,55]. Improper regulation of NO production can lead to diseases such as septic shock, heart disease, arthritis, and diabetes. 

Patients with a variety of cancers and some viral diseases excrete relatively large amounts of neopterin, formed by dephosphorylation and oxidation of dihydroneopterin triphosphate, an intermediate in biopterin synthesis. This reflects the induction of GTP cyclohydrolase by interferon-y and tumor necrosis factor-a in response to the increased requirement for tetrahydrobiopterin for nitric oxide synthesis (Section 10.4.2). It is thus a marker of ceU-mediated immune reactions and permits monitoring of disease progression (Werner et al., 1993,1998 Berdowska and Zwirska-Korczala, 2001). 

In addition to dietary sources, a significant amount of nitrate is formed endogenously by the metabolism of nitric oxide - 1 mg per kg of body weight per day (about the same as the average dietary intake), increasing 20-fold in response to inflammation and immune stimulation. There is considerable secretion of nitrate in saliva, and up to 20% of this may be reduced to nitrite by oral bacteria. Under the acidic conditions of the stomach, nitrite can react with amines in foods to form carcinogenic N-nitrosamines, although it is not known to what extent this occurs in vivo. 

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