A METALLOPORPHYRIN SUPEROXIDE-DISMUTASE MIMETIC PROTECTS AGAINST PARAQUAT-INDUCED LUNG INJURY IN-VIVO

We employed a low-molecular-weight metalloporphyrin superoxide dismuta se mimetic, MnTBAP, to protect mice against a known pulmonary toxicant , paraquat. Paraquat creates toxicity by elevating intracellular level s of superoxide through redox cycling with cellular diaphorases and ox ygen. In vitro, paraquat-induced cell injury can be attenuated by MnTB AP. We assessed whether inhaled MnTBAP would protect whole animals fro m a single ip dose of paraquat, Mice were given either saline (10 ml/k g, ip) or paraquat (45 mg/kg, ip) and 30 min later exposed to aerosoli zed saline or MnTBAP (5 mM) for 30 min twice daily, Mice were killed 4 8 hr after paraquat treatment, Lung injury was assessed by measuring l actate dehydrogenase (LDH), protein, and percentage polymorphonuclear leukocytes (PMN) in bronchoalveolar lavage (BAL) fluid and by histopat hology, Paraquat treatment increased levels of BAL fluid LDH, protein, and number of PMNs and produced extensive blebbing of the type I epit helium, MnTBAP reduced lung injury as indicated by lower LDH levels, p rotein levels, and PMN influx in BAL fluid. This correlated with the r eduction of type I epithelial damage in the group of mice that receive d paraquat, These data suggest that metalloporphyrins may be effective therapeutic agents against pathologies that involve overproduction of reactive oxygen species. (C) 1996 Academic Press, Inc.