Amyl, butyl, isobutyl, and cyclohexyl nitrites are volatile chemicals, which are abused by inhalation. Abuse of nitrite inhalants is particularly widespread among homosexuals and, to a lesser extent, among adolescents. The role of nitrite abuse as a possible co-factor in the spread of acquired immunodeficiency syndrome (AIDS) or in Kaposi's sarcoma in AIDS patients has been suggested by epidemiological data. Experimentation supported by the current funding cycle of this grant suggests by that inhalation of isobutyl nitrite severely impaired both antibody and cell-mediated immunity. Using a mouse model which approximated the exposure of habitual abusers, isobutyl nitrite inhibited the induction of T-dependent antibodies and cytotoxic T lymphocytes (CTL) and also macrophage tumoricidal activity. Further study showed that exposure to the inhalant apparently affected B and T cell responses indirectly through effects on accessory cells. Several macrophage activities were modulated by the inhalant, including gamma-interferon induced production of nitric oxide and tumor necrosis factor-a (TNF-a) and intracellular calcium flux. The present renewal proposal will expand this investigation to examine more closely the effects of isobutyl nitrite toxicity in terms of immune function. The possible role of the immunomodulator, nitrite toxicity in terms of immune immunotoxicity by nitrite inhalants will be evaluated by comparing inhalant immunotoxicity with that of authentic nitric oxide gas. The propensity of isobutyl nitrite to form nitric oxide in vitro and in vivo will be measured. In addition, a new, currently available nitrite inhalant, cyclohexyl nitrite, will be studied for immunotoxicity. Cyclohexyl nitrite was designed to evade current legal restrictions and, hence, little is known about adverse effects of this compound. The mechanisms of immunotoxicity by the inhalants will be extended to determine if exposure causes cell death by apoptosis. Effects of the inhalant on macrophage functions, including suppressor activity, accessory cell function, inducible nitric oxide production, cytokine production, and second messenger activities will be examined. The observed reductions in two separate cell-mediated immune mechanisms following exposure to isobutyl nitrite suggests that exposure will lower resistance to infectious agents and tumor growth. This will be evaluated using models of resistance to the growth of the intracellular bacteria, tumor cell growth and clearance in the lung, and retrovirus replication using a murine AIDS model.
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