Carbon monoxide provides protection against hyperoxic lung injury

Findings in recent years strongly suggest that the stress-inducible gene he me oxygenase (HO)-1 plays an important role in protection against oxidative stress. Although the mechanism(s) by which this protection occurs is poorl y understood, we hypothesized that the gaseous molecule carbon monoxide (CO ), a major byproduct of heme catalysis by MO-I, may provide protection agai nst oxidative stress. We demonstrate- here that animals exposed to a low co ncentration of CO exhibit a marked tolerance to lethal concentrations of hy peroxia in vivo. This increased survival was associated with highly signifi cant attenuation of hyperoxia-induced lung injury as assessed by the volume of pleural effusion, protein accumulation in the airways, and histological analysis. The lungs were completely devoid of lung airway and parenchymal inflammation, fibrin deposition, and pulmonary edema in rats exposed to hyp eroxia in the presence of a low concentration of CO. Further more, exogenou s CO completely protected against hyperoxia-induced lung injury in rats in which endogenous HO enzyme activity was inhibited with tin protoporphyrin, a selective inhibitor of HO. Rats exposed to CO also exhibited a marked att enuation of hyperoxia-induced neutrophil infiltration into the airways and total lung apoptotic index. Taken together, our data demonstrate, for the f irst time, that CO can be therapeutic against-oxidative stress such as hype roxia and highlight possible mechanism(s) by which CO may mediate these pro tective effects.