Inhibition of nitric oxide synthase attenuates NNMU-induced alveolar injury in vivo

The purpose of this study was to determine if the acute alveolar injury induced by subcutaneous injections of N-nitroso-N-methylurethane (NNMU) in rats is mediated by nitric oxide (NO .). We show that intraperitoneal injections of the NO . synthase (NOS) inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine significantly attenuate the NNMU-induced alveolar injury as assessed by I) normalization of the alveolar-arterial Oz difference, 2) attenuation of the lowered phospholipid-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 alveolar space. Injections of N-omega-nitro-D-arginine methyl ester, the inactive stereo-isoform of L-NAME, did not affect the acute lung injury. Western blot analysis of whole lung homogenates demonstrate an elevated expression of transcriptionally inducible, Ca2+-independent NOS (iNOS) in NNMU-injected rats compared with control saline-injected rats. 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.