EXOGENOUS AND ENDOGENOUS TRANSFORMING GROWTH FACTORS-BETA INFLUENCE ELASTIN GENE-EXPRESSION IN CULTURED LUNG FIBROBLASTS

Elastin, an important structural protein of the extracellular matrix, confers elastic properties on the pulmonary alveolar interstitium. In the alveolar wall, elastin is primarily produced postnatally by fibrob lasts. The mechanisms that regulate lung fibroblast (LF) elastin gene expression have not been completely defined, although both transcripti onal and posttranscriptional mechanisms appear to be involved. Transfo rming growth factors-beta (TGF-beta s) have been shown to increase ela stin production by cultured neonatal rat LF. Analyses of elastin gene transcription and mRNA stability indicate that exogenous TGF-beta(1) i ncreases the half-life of tropoelastin mRNA by 1.5-fold and does not a lter elastin gene transcription. Interference with the functions of en dogenous TGF-beta(1) in cultured LF, through the addition of neutraliz ing antibodies or antisense oligodeoxynucleotides, decreases tropoelas tin and tropoelastin mRNA production by these cells. The content of to tal (latent plus active) TGF-beta s was approximately 4.5-fold greater in lungs obtained from rats on postnatal day 8 than in lungs obtained from adults. These findings indicate that endogenous TGF-beta s, in c ultured LF, regulate elastin gene expression, most likely by a posttra nscriptional mechanism. Since others have shown that elastin mRNA appe ars to have a longer half-life in neonatal than in adult rat lungs, we hypothesize that the higher content of TGF-beta s could contribute to the greater elastin mRNA stability in neonatal lungs.