NITRIC-OXIDE REGULATION OF SUPEROXIDE-DEPENDENT LUNG INJURY - OXIDANT-PROTECTIVE ACTIONS OF ENDOGENOUSLY PRODUCED AND EXOGENOUSLY ADMINISTERED NITRIC-OXIDE

The influence of endogenous cell (NO)-N-. production and (NO)-N-. deri ved from exogenous sources on oxidant injury to cultured fetal rat lun g alveolar epithelium and an animal model of pulmonary oxidant injury was examined. Confluent fetal rat alveolar epithelial cell monolayers were stimulated to produce (NO)-N-. after treatment with a combination of cytokines (IL-1 beta, TNF-alpha, IFN-gamma), LPS and zymosan-activ ated serum (CZ), Cell injury, assessed by C-14-adenine release was sig nificantly increased compared to basal and CZ-induced cells after inhi bition of (NO)-N-. synthesis by L-NMMA. Cell monolayer macromolecule b arrier function was determined by the rate of diffusion of I-125-album in from the apical to basolateral side of monolayers Following exposur e to CZ and/or O-2(.-) generated by xanthine oxidase + lumazine (XO), endogenous cell (NO)-N-. production and exogenously administered (NO)- N-. (from (NO)-N-. donors S-nitrosyl-glutathione and S-nitroso-N-acety lpenicillamine) significantly inhibited the increased monolayer permea bility induced by exposure to reactive oxygen species. Furthermore, in halation of 5-10 ppm of (NO)-N-. significantly reduced the toxicity of > 95% oxygen to adult rats. We conclude that when cultured pulmonary epithelial cells and lung tissue in vivo are subjected to inflammatory mediators or acute oxidative stress, (NO)-N-. can play a protective r ole by inhibiting O-2(.-)-dependent toxicity.