INSULIN INHIBITS SURFACTANT PROTEIN-A AND PROTEIN-B GENE-EXPRESSION IN THE H441 CELL-LINE

Fetuses of mothers with uncontrolled gestational diabetes have an incr eased risk of developing neonatal respiratory distress syndrome and ar e frequently hyperinsulinemic, thus it has been proposed that high lev els of insulin delay fetal lung maturation. We have shown previously t hat insulin inhibits the accumulation of mRNA for the surfactant-assoc iated proteins A and B (SP-A and SP-B) in human fetal lung explants ma intained in vitro. To test the hypothesis that the inhibitory effects of insulin on the surfactant proteins are the result of a direct actio n of insulin on the lung epithelial cell, we evaluated the effects of insulin in the H441 cell line, a human pulmonary adenocarcinoma cell l ine that expresses SP-A and SP-B mRNA. We observed that insulin treatm ent for 48 h decreased SP-A mRNA and protein levels in a concentration -dependent manner when compared to controls. The inhibitory effect of insulin on SP-A mRNA levels was apparent as early as after 4 h of expo sure. SP-B mRNA levels were also significantly decreased by insulin in a concentration-dependent manner. Insulin, at 2.5 mu g/ml, inhibited SP-A gene transcription by approx. 67%, and inhibited SP-B gene transc ription by about 32%. There was no significant effect of insulin on SP -A or SP-B mRNA stability. Thus, we have observed a pattern of insulin inhibition of SP-A and SP-B gene expression in the H441 lung epitheli al cell line similar to that previously observed in human fetal lung e xplants, which are comprised of both epithelial and mesenchymal cells. Our findings provide further evidence that insulin may delay fetal lu ng maturation by inhibiting SP-A and SP-B gene expression. Furthermore , our findings suggest that the inhibitory effects of insulin are, at least partially, the result of a direct action on the lung epithelial cell. (C) 1998 Elsevier Science B.V. All rights reserved.