Biochemical mechanisms for the attenuation of bleomycin-induced lung fibrosis by treatment with niacin in hamsters: the role of NAD and ATP.
Treatment with niacin (NA), a precursor of NAD, has been shown to attenuate collagen accumulation in the bleomycin (BL) hamster model of lung fibrosis. This study investigated the effects of NA on lung levels of NAD, ATP, ADP, and AMP during various stages of lung fibrosis caused by intratracheal (IT) instillation of BL in hamsters. Niacin (500 mg/kg, IP) or saline (SA, IP) was given daily two days prior to and every day after the IT administration of BL (7.5 U/5 mL/kg) or an equivalent volume of sterile isotonic saline. Hamsters were sacrificed at 1, 4, 7, 10, and 14 days after BL or saline treatment. Lung NAD, ATP, ADP, and AMP were separated and quantitated using C-18 reverse-phase HPLC coupled with UV detection. The lung ATP content of the SABL groups was significantly (p < or = .05) increased at 1, 7, 10, and 14 days, peaking at 7 days to 210 +/- 20% of the SASA group. The hamsters in NABL groups also had significant increases in ATP levels at 7, 10, and 14 days, peaking to 172 +/- 18% of the NASA group at 7 days. ATP levels in the NABL groups were significantly higher than SABL groups at 10 and 14 days. There were small changes in the lung levels of ADP and AMP among the various treated groups. The lung NAD content of the SABL group was significantly decreased compared to the SASA group at 7 and 10 days, with a nadir of 66 +/- 13% at 10 days. The lung NAD content in the NABL group was significantly higher than that of the SABL group at 10 and 14 days. There was no significant difference in lung NAD content between the NABL and NASA groups. The results of this study suggest that depletions of NAD and ATP play a pivotal role in the pathogenesis of BL-induced lung toxicity, and treatment with NA minimizes this toxicity by increasing and/or maintaining the intracellular levels of NAD and ATP of the lungs.
O'Neill
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Department of Veterinary Pharmacology and Toxicology, University of California, Davis 95616.
Giri
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D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*
D009243:NAD; D001761:Bleomycin; D009525:Niacin; D000249:Adenosine Monophosphate; D009249:NADP; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003094:Collagen; D006909:Hydroxyproline; D002118:Calcium