Antagonistic effects of pyrrolidine dithiocarbamate and N-acetyl-L-cysteine on surfactant protein A and B mRNAs

Pulmonary surfactant, a mixture of phospholipids and specific associated pr oteins, reduces surface tension at the air-liquid interface of the lung and protects the large epithelial surface of the lung from infectious organism s. Surfactant proteins, SP-A and SP-B, are required for normal surfactant f unction. In the current work, increased levels of oxidized glutathione (GSS G) are demonstrated at doses of pyrrolidine dithiocarbamate (PDTC) which de crease SP-A and SP-B mRNAs, suggesting that cellular oxidation reduces surf actant protein expression. Similarly, reduction of SP-A and SP-B mRNA level s 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 pulmon ary 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-cyst eine (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 o f the pulmonary epithelium to oxidant stress and may be reversed by the ant ioxidant NAC.