The differential expression of apoptosis factors in the alveolar epithelium is redox sensitive and requires NF-kappa B (RelA)-selective targeting

Fetal alveolar type II (fATII) epithelial cells were used to evaluate the r ole of signaling factors involved in oxidative stress-induced programmed ce ll death (PCD; apoptosis). Bcl-2, an antiapoptotic proto-oncogene, showed m aximum abundance in hypoxia and mild reoxygenation, but declined thereafter . The Bcl-2 counterpart, Bax, which promotes PCD, displayed an increasing l ogarithmic profile with ascending Delta pO(2) regimen, such that the ratio of Bcl-2/Bax decreased as pO(2) increased. The expression of p53, a cell cy cle regulator, paralleled Bax abundance. Pretreatment of fATII cells with L -buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylc ysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutath ione (GSH), enhanced Bax and p53 expression over Bcl-2. The GSH analogue, g amma-glutamylcysteinyl-ethyl ester, down-regulated Bax/p53 abundance but re stored that of Bcl-2, thereby increasing Bcl-2/Bax. The antioxidant and GSH precursor N-acetyl-L-cysteine favored Bcl-2 at the expense of Bax/p53, whe reas pyrrolidine dithiocarbamate induced Bax against Bcl-2, with mild effec t on p53. Sulfasalazine, a potent and specific inhibitor of NF-kappa B, ind uced Bax at the expense of Bcl-2, in a p53-dependent manner. We conclude th at the differential expression of signaling factors involved in PCD in the alveolar epithelium is redox-sensitive and mediated, at least in part, by a negative feedback mechanism transduced by NF-kappa B. (C) 2000 Academic Pr ess.