A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo.
We employed a low-molecular-weight metalloporphyrin superoxide dismutase mimetic, MnTBAP, to protect mice against a known pulmonary toxicant, paraquat. Paraquat creates toxicity by elevating intracellular levels of superoxide through redox cycling with cellular diaphorases and oxygen. In vitro, paraquat-induced cell injury can be attenuated by MnTBAP. We assessed whether inhaled MnTBAP would protect whole animals from a single i.p. dose of paraquat. Mice were given either saline (10 ml/ kg, i.p.) or paraquat (45 mg/kg, i.p.) and 30 min later exposed to aerosolized saline or MnTBAP (5 mM) for 30 min twice daily. Mice were killed 48 hr after paraquat treatment. Lung injury was assessed by measuring lactate dehydrogenase (LDH), protein, and percentage polymorphonuclear leukocytes (PMN) in bronchoalveolar lavage (BAL) fluid and by histopathology. Paraquat treatment increased levels of BAL fluid LDH, protein, and number of PMNs and produced extensive blebbing of the type I epithelium. MnTBAP reduced lung injury as indicated by lower LDH levels, protein levels, and PMN influx in BAL fluid. This correlated with the reduction of type I epithelial damage in the group of mice that received paraquat. These data suggest that metalloporphyrins may be effective therapeutic agents against pathologies that involve overproduction of reactive oxygen species.
Day
B J
BJ
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Crapo
J D
JD
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051379:Mice; D010269:Paraquat / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D000931:Antidotes; D008665:Metalloporphyrins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D010269:Paraquat