Bleomycin-induced pulmonary fibrosis in the rat. Prevention with an inhibitor of collagen synthesis.
Pharmacologic treatment of pulmonary fibrosis has been limited to the use of corticosteroids occasionally combined with other immunosuppressive agents. We tested the ability of a proline analogue that is a potent inhibitor of collagen biosynthesis to prevent the manifestations of bleomycin-induced pulmonary fibrosis in an animal model. Bleomycin sulfate was administered by intratracheal instillation to produce pulmonary fibrosis in male Fischer 344 rats. After 28 days lungs from bleomycin-treated animals had histologic, biochemical, and functional alterations consistent with pulmonary fibrosis. Vital capacity and compliance were reduced to 62% and 41% of their respective control values. Lung prolyl hydroxylase activity doubled during the first week after bleomycin, at a time when total lung collagen content remained unchanged. Thereafter total lung collagen content slowly rose to 72% above control values at 28 days. We administered the proline analogue DHP at a dose that completely inhibited the elevated levels of lung prolyl hydroxylase activity. Pulmonary collagen content of animals treated with DHP was only minimally elevated, and functional abnormalities were reduced. Pulmonary compliance increased significantly from 0.25 to 0.44 ml/cm of H2O, and vital capacity increased from 3.94 to 5.65 ml. These studies suggest that proline analogues offer potential for modifying the manifestations of pulmonary fibrosis that occur as a consequence of acute lung injury. Elevation of lung prolyl hydroxylase activity is an early even that serves as a useful index of the acute lung injury produced by bleomycin.
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D003094:Collagen / Q000096:biosynthesis*; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344
D001761:Bleomycin; C002195:3,4-dehydroproline; D003094:Collagen; D011392:Proline; D011393:Procollagen-Proline Dioxygenase