INHIBITION OF ALVEOLAR TYPE-II CELL ATP AND SURFACTANT SYNTHESIS BY NITRIC-OXIDE

Alveolar type II (ATII) cells, are often exposed to increased concentr ation of endogenous and exogenous nitric oxide (. NO). Exposure of fre shly isolated rat ATII cells for 2 h to 1-3 mu M . NO, generated by S- nitroso-N-penicillamine (SNAP), spermine NONOate, or 3-morpholino-sydn onimine (SIN-1) in the presence of superoxide dismutase, resulted in s imilar to 60% decrease in the rate of surfactant synthesis, as measure d by the rate of incorporation of [methyl-H-3]choline into phosphatidy lcholine, and 60-80% inhibition of cellular ATP levels, as determined by bioluminescence. Similar results were obtained after incubation of ATII cells with authentic peroxynitrite (0.5 mM) but not SIN-1, a puta tive generator of peroxynitrite. Addition into the medium of oxyhemogl obin (20 mu M), which scavenged . NO, or enhancement of ATII glutathio ne levels by preincubation with glutathione ester (5 mM) totally preve nted the NONOate (100 mu M) inhibition of cellular ATP. In contrast to the in vitro findings, normal levels of ATP and lipid synthesis were measured in ATII cells isolated from the lungs of rats that breathed . NO gas (80 ppm) in 21% O-2 for 2 h (n = 4). This lack of effect may b e due either to the presence of various antioxidants (such as glutathi one) in the epithelial lining fluid or to the relatively low concentra tions of . NO reaching the alveolar epithelium. We conclude that . NO and peroxynitrite, at concentrations likely to be encountered in vivo during inflammation, decrease ATII cell energy stores and surfactant s ynthesis, which may lead to derangement of important physiological fun ctions.