title: Antagonistic effects of pyrrolidine dithiocarbamate and N-acetyl-L-cysteine on surfactant protein A and B mRNAs.
abstract: Pulmonary surfactant, a mixture of phospholipids and specific associated proteins, reduces surface tension at the air-liquid interface of the lung and protects the large epithelial surface of the lung from infectious organisms. Surfactant proteins, SP-A and SP-B, are required for normal surfactant function. In the current work, increased levels of oxidized glutathione (GSSG) are demonstrated at doses of pyrrolidine dithiocarbamate (PDTC) which decrease SP-A and SP-B mRNAs, suggesting that cellular oxidation reduces surfactant protein expression. Similarly, reduction of SP-A and SP-B mRNA levels following accumulation of GSSG induced by glutathione reductase inhibitor 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), supports the hypothesis that surfactant protein synthesis is reduced in response to oxidation of pulmonary epithelial glutathione. Concurrent induction of apolipoprotein J (apoJ) mRNA by PDTC demonstrates the selectivity of pulmonary gene regulation by the dithiocarbamate. In contrast, the glutathione precursor N-acetyl-l-cysteine (NAC) prevented PDTC-dependent increase in GSSG/GSH ratio, inhibition of SP-A and -B mRNAs, and induction of apoJ. Insufficiency of SP-A and -B, which occurs in inflammatory lung diseases, may result from the exposure of the pulmonary epithelium to oxidant stress and may be reversed by the antioxidant NAC.
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, New York 14642, USA.
authors.forename: R
authors.initials: R
authors.lastname: Khalak
authors.forename: H L
authors.initials: HL
authors.lastname: Huyck
authors.forename: G S
authors.initials: GS
authors.lastname: Pryhuber
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D015152:Blotting, Northern; D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D051152:Clusterin; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D018832:Molecular Chaperones; D011510:Proteolipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D006861:Hydrogen Peroxide; D005980:Glutathione Reductase; D012260:Ribonucleases; D005978:Glutathione; D002330:Carmustine; D019803:Glutathione Disulfide; D000111:Acetylcysteine