Amelioration of bleomycin-induced lung fibrosis by treatment with the platelet activating factor receptor antagonist WEB 2086 in hamsters.

Abstract

Therapeutic use of bleomycin, an antineoplastic drug, is complicated by the development of a dose-dependent lung toxicity leading to fibrosis. This study tested the effectiveness of a platelet activating factor (PAF) receptor antagonist, WEB 2086, against bleomycin (BLEO)-induced lung fibrosis in hamsters. The animals were assigned to four groups: (1) saline (SA) + SA, (2) WEB 2086 (WEB) + SA, (3) SA + BLEO, and (4) WEB + BLEO. Sterile isotonic saline or WEB 2086 (10 mg/kg IP) was administered daily for the duration of the study starting 2 days prior to intratracheal (IT) instillation of saline or bleomycin (2.5, 2.0, and 1.5 units/kg 5 mL-1) in three consecutive doses at weekly intervals. The animals were killed at 21 days after the last IT instillation and their lungs were processed for various studies. The lung hydroxyproline levels in SA + SA, WEB + SA, SA + BLEO, and WEB + BLEO groups were 932 +/- 31, 943 +/- 48, 1302 +/- 72, and 964 +/- 63 micrograms/lung, respectively. The lung myeloperoxidase (MPO) activity and malondialdehyde equivalent, an index of lipid peroxidation, in the corresponding groups were 10 +/- 2, 8 +/- 2, 14 +/- 3, and 5 +/- 1 units/lung and 93 +/- 7, 77 +/- 5, 102 +/- 8, and 75 +/- 6 nmol/lung, respectively. The lung prolyl hydroxylase activity in the WEB + SA, SA + BLEO, and WEB + BLEO groups was 130.1 +/- 7.7, 236.2 +/- 12.8, and 138.1 +/- 7.0% of the SA + SA control group (8.3 x 10(4) dpm/lung 30 min-1), respectively. Daily treatment with WEB 2086 caused significant (p < or = .05) reductions in the BLEO-induced increases in the lung hydroxyproline content, prolyl hydroxylase and MPO activities, lipid peroxidation, and acid phosphatase activity of the BALF supernatant. Although daily treatment with WEB 2086 reduced the bleomycin-induced increases in the BALF total and neutrophil cell counts, BALF supernatant protein, and morphometric estimates of the lesions, these parameters were not significantly different from those of the SA-BLEO group. Histopathologic studies revealed that there were no lesions of alveolar consolidation and fibrosis in the lungs of WEB + BLEO group as compared with the SA + BLEO group. The results suggest that PAF is involved in the BLEO-induced lung fibrosis and that PAF-receptor antagonist may therefore be potentially useful in the attenuation of lung fibrosis caused by bleomycin.