Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin

Oxidative stress plays an important role in the development of fibrotic res ponses in the lung. However, it is not clear whether inhibiting oxidative s tress with antioxidants can attenuate fibrotic processes in the lung. The o bjective of these studies was to test whether the catalytic antioxidant por phyrin manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) could p rotect mice against bleomycin-induced lung fibrosis. A 10 mg/kg intraperito neal dose of MnTBAP was established as safe and had a serum and lung half-l ife of 9.5 h in mice. Based on this data, four groups of mice were given on e dose of bleomycin (3.2 U/kg, intratracheal) or saline and MnTBAP (5 mg/kg , intraperitoneal) or saline twice daily for 14 d. Lung fibrosis was assess ed by measuring (1) lung hydroxyproline content as an index of collagen acc umulation, (2) airway dysfunction by whole body plethysmography, and (3) hi stopathology. Bleomycin produced a 20% loss in body weight that was only 10 % in the bleomycin/MnTBAP group. Bleomycin produced a twofold increase in h ydroxyproline content that was decreased 23% by MnTBAP. Bleomycin produced a twofold increase in airway dysfunction that was also attenuated 30% by Mn TBAP. Histopathologic analysis of the lungs of mice treated with bleomycin demonstrated a severe fibrotic response that was attenuated 28% by MnTBAP. Future studies on the oxidant mechanisms that MnTBAP is affecting in this b leomycin model of lung fibrosis may shed light on potential new therapeutic approaches for treating interstitial lung diseases.