The differential expression of apoptosis factors in the alveolar epithelium is redox sensitive and requires NF-kappaB (RelA)-selective targeting.
Fetal alveolar type II (fATII) epithelial cells were used to evaluate the role of signaling factors involved in oxidative stress-induced programmed cell death (PCD; apoptosis). Bcl-2, an antiapoptotic proto-oncogene, showed maximum abundance in hypoxia and mild reoxygenation, but declined thereafter. The Bcl-2 counterpart, Bax, which promotes PCD, displayed an increasing logarithmic profile with ascending DeltapO(2) regimen, such that the ratio of Bcl-2/Bax decreased as pO(2) increased. The expression of p53, a cell cycle regulator, paralleled Bax abundance. Pretreatment of fATII cells with l-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), enhanced Bax and p53 expression over Bcl-2. The GSH analogue, gamma-glutamylcysteinyl-ethyl ester, down-regulated Bax/p53 abundance but restored 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, whereas pyrrolidine dithiocarbamate induced Bax against Bcl-2, with mild effect on p53. Sulfasalazine, a potent and specific inhibitor of NF-kappaB, induced Bax at the expense of Bcl-2, in a p53-dependent manner. We conclude that 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-kappaB.
Haddad
J J
JJ
Oxygen Signaling Group, University of Dundee, Dundee, Scotland, DD1 9SY, United Kingdom.
Land
S C
SC
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D053938:DNA Fragmentation; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
D000975:Antioxidants; D004151:Dipeptides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D013859:Thiocarbamates; D051028:bcl-2-Associated X Protein; C067744:N-gamma-glutamylcysteine ethyl ester; C020972:pyrrolidine dithiocarbamic acid; D012460:Sulfasalazine; D019328:Buthionine Sulfoximine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D010100:Oxygen; D000111:Acetylcysteine