Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats

In this study, the biochemical mechanisms by which N-nitroso-N-methyluretha ne (NNMU) induces acute lung injury are examined. Polymorphonuclear neutrop hil infiltration into the lungs first appears in the bronchoalveolar lavage (BAL) fluid 24 h after NNMU injection (10.58 +/- 3.00% of total cells; P < 0.05 vs. control animals). However, NNMU-induced elevation of the alveolar -arterial O-2 difference requires 72 h to develop. Daily intraperitoneal in jections of the inducible nitric oxide (. NO) synthase (iNOS)-selective inh ibitor aminoguanidine (AG) initiated 24 h after NNMU administration improve the survival of NNMU-treated animals. However, AG administration initiated 48 or 72 h after NNMU injection does not significantly improve the surviva l of NNMU-treated animals. These results suggest that . NO participates in events that occur early in NNMU-induced acute lung injury. BAL cells isolat ed from rats 24 and 48 h after NNMU injection produce elevated . NO and exp ress iNOS during a 24-h ex vivo culture. AG attenuates . NO production but does not affect iNOS expression, whereas actinomycin D prevents iNOS expres sion and attenuates . NO production by BAL cells during this ex vivo cultur e, These results suggest that NNMU-derived BAL cells can stimulate iNOS exp ression and . NO production during culture. In 48-h NNMU-exposed rats, iNOS expression is elevated in homogenates of whole lavaged lungs but not in BA L cells derived from the same lung. These findings suggest that the pathoge nic mechanism by which NNMU induces acute lung injury involves BAL cell sti mulation of iNOS expression and . NO production in lung tissue.