The autocrine/paracrine growth mechanism has been implicated in the regulation of bronchial epithelial cell proliferation. By inhibiting the expression of the transforming growth factor-alpha (TGF-alpha) gene product, vitamin A is able to suppress the proliferation of tracheobronchial epithelial cells in culture. Similar repressions in TGF-alpha mRNA levels by retinol were observed in airway explant cultures and in a cell line immortalized from normal human bronchial epithelial cells. Both the nuclear run-on transcriptional assay and the transfection study with the chimeric construct of the TGF-alpha promoter and chloramphenicol acetyltransferase reporter gene partly suggest a transcriptional downregulation mechanism of TGF-alpha gene expression by the retinol treatment; however, this inhibition at the transcriptional level cannot account for the total inhibition at the mRNA level. These results suggest that a downregulation of the expression of the TGF-alpha gene at the transcriptional and post-transcriptional levels by vitamin A may precede the essential event associated with the homeostasis of normal conducting airway epithelium.