Effects of dibutyrylcyclic adenosine monophosphate on bleomycin-induced lung toxicity in hamsters.
Cyclic nucleotides play an important role in the regulation of fibroblast proliferation and collagen metabolism. In the present study, the antifibrotic potential of dibutyrylcAMP (Bt2cAMP) was evaluated in the bleomycin (BLM)-hamster model of pulmonary fibrosis. Bt2cAMP (10 mg kg-1, s.c.) or saline (SA, s.c.) was given daily two days prior to the first intratracheal (i.t.) dose of BLM or SA and thereafter throughout the study. BLM or SA was instilled i.t. in three consecutive doses (2.5, 2.0 and 1.5 U 5ml-1 kg-1) at weekly intervals. Hamsters were killed at 7, 14 and 20 days after the third i.t. instillation. Bt2cAMP significantly reduced the contents of lung hydroxyproline and lung thiobarbituric acid reactive substance equivalents in BLM-treated animals at 7 and 14 days. Bt2cAMP significantly elevated lung superoxide dismutase activity in BLM-treated animals at 7 days. Lung prolyl hydroxylase activity was significantly elevated at 14 and 20 days in SABLM- and Bt2cAMPBLM-treated animals. The ratio of cAMP/cGMP was significantly reduced at all time points in SABLM-treated animals but only at 7 and 14 days in Bt2cAMPBLM-treated animals. Bt2cAMP caused no significant changes in lung calcium and calmodulin levels and protein content of the bronchoalveolar lavage. BLM significantly increased various inflammatory cell counts in the lavage at all three time points. The cell counts in the Bt2cAMPBLM groups were generally lower at 7 days and higher at 20 days than those of the SABLM groups. Histological evaluation showed that the lungs of Bt2cAMPBLM-treated hamsters progressed from an inflammatory cell lesion to a fibrotic lesion at a slower rate than the SABLM groups. It was concluded that Bt2cAMP attenuated BLM-induced pulmonary fibrosis in hamsters in part by delaying the acute phase of the inflammatory reaction.
O'Neill
C A
CA
Department of Veterinary Pharmacology and Toxicology, University of California, Davis 95616.
Giri
S N
SN
Wang
Q
Q
Perricone
M A
MA
Hyde
D M
DM
D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003994:Bucladesine / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism
D001761:Bleomycin; D003994:Bucladesine; D000242:Cyclic AMP; D013482:Superoxide Dismutase; D006152:Cyclic GMP; D006909:Hydroxyproline