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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA006662-04
Application #
2118857
Study Section
Sociobehavioral Subcommittee (DAAR)
Project Start
1991-06-01
Project End
1997-05-31
Budget Start
1994-06-01
Budget End
1995-05-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Soderberg, L S F; Ponnappan, U; Roy, A et al. (2004) Production of macrophage IL-1beta was inhibited both at the levels of transcription and maturation by caspase-1 following inhalation exposure to isobutyl nitrite. Toxicol Lett 152:47-56
Ponnappan, Usha; Yull, Fiona E; Soderberg, Lee S F (2004) Inhaled isobutyl nitrite inhibited macrophage inducible nitric oxide by blocking NFkappaB signaling and promoting degradation of inducible nitric oxide synthase-2. Int Immunopharmacol 4:1075-82
Soderberg, Lee S F; Ponnappan, Usha (2002) Cytotoxicity by nitrite inhalants is not related to peroxynitrite formation. Toxicol Lett 132:37-45
Ponnappan, U; Soderberg, L S (2001) Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite. J Leukoc Biol 69:639-44
Guo, G L; Rose, D; Flick, J T et al. (2000) Acute exposure to the abused inhalant, isobutyl nitrite, reduced T cell responsiveness and spleen cellularity. Toxicol Lett 116:151-8
Soderberg, L S; Roy, A; Flick, J T et al. (2000) Nitrite inhalants spontaneously liberate nitric oxide, which is not responsible for the immunotoxicity in C57BL/6 mice. Int J Immunopharmacol 22:151-7
Soderberg, L S (1999) Increased tumor growth in mice exposed to inhaled isobutyl nitrite. Toxicol Lett 104:35-41
Soderberg, L S; Flick, J T (1997) Acute blood toxicity of the abused inhalant, cyclohexyl nitrite. Int J Immunopharmacol 19:305-10
Soderberg, L S; Flick, J T; Barnett, J B (1996) Leukopenia and altered hematopoietic activity in mice exposed to the abused inhalant, isobutyl nitrite. Exp Hematol 24:848-53
Soderberg, L S; Flick, J T; Barnett, J B (1996) Acute inhalation exposure to isobutyl nitrite causes nonspecific blood cell destruction. Exp Hematol 24:592-6

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