Hypoxia downregulates tropoelastin gene expression in rat lung fibroblastsby pretranslational mechanisms

Elastolytic lung injury disrupts cell barriers, flooding alveoli and produc ing regional hypoxia. Abnormal O-2 tensions may alter repair of damaged ela stin fibers. To determine the effect of hypoxia on extravascular elastin fo rmation, we isolated rat lung fibroblasts and cultured them under a variety of O-2 conditions. Hypoxia downregulated tropoelastin mRNA in a dose- and time-related fashion while upregulating glyceraldehyde-3-phosphate dehydrog enase mRNA levels. The changes in tropoelastin gene expression were not due to cell toxicity as measured by chromium release and cell proliferation st udies. Neither cycloheximide nor actinomycin D abrogated this effect. Hypox ia induced early decreases in tropoelastin mRNA stability; minor suppressio n of gene transcription occurred later. When returned to 21% O-2, tropoelas tin mRNA recovered to control levels in part by upregulating tropoelastin g ene transcription. Taken together, these data indicate that hypoxia regulat es tropoelastin gene expression and may alter repair of acutely injured lun g.