Amyl, butyl, and isobutyl nitrites are volatile chemicals, which are abused by inhalation. Abuse of nitrite inhalants is particularly widespread among homosexuals, but is also becoming widespread among adolescents. The role of nitrite abuse as a possible co-factor in the spread of acquired immuno-deficiency syndrome (AIDS) or in Kaposi's sarcoma in AIDS patients has been debated, but no firm conclusion can be drawn, based on published data. Data, obtained in this laboratory, suggests that mouse inhalation of isobutyl nitrite at levels approximating the exposure of habitual abusers caused severely impaired T-dependent antibody induction and T cell proliferative responses. Such an immunodeficiency could make an individual more susceptible to a variety of infectious agents, including human immunodeficiency virus (HIV). The present study will investigate the extent of isobutyl nitrite toxicity in terms of immune function. To do this, the panel of standard immunological assays recommended by the National Toxicology Program (Tier I and II) for screening immunotoxic xenobiotics will be used. Cell separation and functional assays will be used to determine the extent to which different immune cell types are altered by immunotoxic exposure to the nitrite inhalant. In order to evaluate the risk of exposure the minimal isobutyl exposures which cause immunotoxicity will be established using acute (1 day), subchronic (14 days), and chronic (8 weeks) dosing regimens. The time to recovery of immunocompetence following immunotoxic exposures will be determined. The mechanisms involved in isobutyl nitrite immunotoxicity will be examined to characterize the extent of the toxicity and perhaps suggest approaches to therapeutic treatment. Mechanistic studies will include the investigation of toxic effects on cell cycle and on immune cell activities, such as cytokine production and cell responses to cytokines. In addition, mechanistic studies will examine immunotixic effects on signal transduction through modulation of calcium influx, cyclic nucleotides, and protein kinase C.
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