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 production and .NO derived from exogenous sources on oxidant injury to cultured fetal rat lung alveolar epithelium and an animal model of pulmonary oxidant injury was examined. Confluent fetal rat alveolar epithelial cell monolayers were stimulated to produce .NO after treatment with a combination of cytokines (IL-1 beta, TNF-alpha, IFN-gamma), LPS and zymosan-activated serum (CZ). Cell injury, assessed by 14C-adenine release, was significantly increased compared to basal and CZ-induced cells after inhibition of .NO synthesis by L-NMMA. Cell monolayer macromolecule barrier function was determined by the rate of diffusion of 125I-albumin from the apical to basolateral side of monolayers. Following exposure to CZ and/or O2.- generated by xanthine oxidase + lumazine (XO), endogenous cell .NO production and exogenously administered .NO (from .NO donors S-nitrosyl-glutathione and S-nitroso-N-acetylpenicillamine) significantly inhibited the increased monolayer permeability induced by exposure to reactive oxygen species. Furthermore, inhalation of 5-10 ppm of .NO 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 can play a protective role by inhibiting O2.(-)-dependent toxicity.
Gutierrez
H H
HH
Department of Pediatrics, University of Alabama at Birmingham 35294, USA.
Nieves
B
B
Chumley
P
P
Rivera
A
A
Freeman
B A
BA
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli; D005333:Fetus; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology* / Q000633:toxicity*; D009603:Nitroso Compounds / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity*; D010100:Oxygen / Q000633:toxicity*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009603:Nitroso Compounds; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D026423:S-Nitroso-N-Acetylpenicillamine; D007371:Interferon-gamma; D015054:Zymosan; D014969:Xanthine Oxidase; D005978:Glutathione; D010396:Penicillamine; D010100:Oxygen