INHIBITION OF NITRIC-OXIDE SYNTHASE ATTENUATES NNMU-INDUCED ALVEOLAR INJURY IN-VIVO

The purpose of this study was to determine if the acute alveolar injur y induced by subcutaneous injections of N-nitroso-N-methylurethane (NN MU) in rats is mediated by nitric oxide (NO .). We show that intraperi toneal injections of the NO . synthase (NOS) inhibitor N-omega-nitro-L -arginine methyl ester (L-NAME) or aminoguanidine significantly attenu ate the NNMU-induced alveolar injury as assessed by I) normalization o f the alveolar-arterial Oz difference, 2) attenuation of the lowered p hospholipid-to-protein ratio in the crude surfactant pellet (CSP), 3) attenuation of the elevated minimal surface tension of the CSP, and 4) attenuation of polymorphonuclear neutrophilic infiltration into the a lveolar space. Injections of N-omega-nitro-D-arginine methyl ester, th e inactive stereo-isoform of L-NAME, did not affect the acute lung inj ury. Western blot analysis of whole lung homogenates demonstrate an el evated expression of transcriptionally inducible, Ca2+-independent NOS (iNOS) in NNMU-injected rats compared with control saline-injected ra ts. NOS inhibitors did not affect NNMU-induced iNOS expression. These investigations demonstrate that the inhibition of NOS attenuates NNMU- induced acute lung injury, suggesting a role for NO in the progression of acute respiratory distress syndrome.