Studies of the effects of alpha-difluoromethylornithine and ethanol on the pathogenesis of bleomycin-induced pulmonary fibrosis in mice.
Both DL-alpha-difluoromethylornithine (DFMO) and ethanol have been reported to inhibit the growth of fibroblasts in cell culture. The objectives of the present study were to determine whether these compounds could be used to inhibit the growth of fibroblasts in vivo, with a bleomycin-induced mouse model of pulmonary fibrosis. DBA/2J mice were given a single endotracheal injection of bleomycin, 10 nmol. In addition to bleomycin (BLM), groups of animals received 2% DFMO in drinking water for 4 days prior to BLM and 18 days after (BLM DFMO), 6% ethanol in drinking water for 7 days prior to BLM and 21 days after (BLM E7), 6% ethanol in drinking water for 21 days initiated on the day of BLM intubation (BLM E), or DFMO, E7, and BLM in combination (BLM DFMO E7). Animals died or were killed 21 days after bleomycin treatment and lungs were evaluated by histopathologic criteria. DFMO failed to alter the incidence or severity of fibrotic lesions, increased the severity of epithelial metaplasia (p less than 0.05), and reduced the lung disease index (from 56.3 to 42.1%, p less than 0.05) and mortality from 83.3 to 41.7% (p less than 0.025). In contrast to the unsatisfactory response to DFMO, pretreatment with ethanol (BLM E7) reduced the incidence of interstitial fibrosis from 91.3 to 71.4% (p less than 0.05) and confluent fibrosis from 73.9 to 20.0% (p less than 0.005). The severity of lesions was also reduced by ethanol, resulting in an 18.5% decrease in interstitial fibrosis, a 25.9% decrease in epithelial metaplasia, and a 55.4% reduction in the lung disease index (all p less than 0.01). However, when ethanol and DFMO were administered in combination, the beneficial effects of ethanol alone were not observed, and only the lung disease index was decreased.
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D000518:Eflornithine; D000431:Ethanol / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008861:Microsomes / Q000187:drug effects; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced*
D001761:Bleomycin; D000431:Ethanol; D009952:Ornithine; D000518:Eflornithine