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Inhibition of Epidermal Growth Factor-like Growth Factor Secretion in Tracheobronchial Epithelial Cells by Vitamin A¹

California Regional Primate Research Center and Department of Internal Medicine, University of California at Davis, Davis, California 95616

Vitamin A deficiency of respiratory tract epithelium results in the phenomenon of squamous cell metaplasia. The mechanisms by which vitamin A regulates airway epithelial cell growth and differentiation are not completely understood. In this study, we focused on the effects of vitamin A (retinol) on growth of human and non-human primate tracheobronchial epithelial (TBE) cells in culture. Retinol and its derivatives have little growth-stimulatory effect on TBE cells that are maintained in primary culture in a serum-free medium supplemented with 6 hormonal supplements: insulin, transferrin, epidermal growth factor (EGF), hydrocortisone, cholera toxin, and bovine hypothalamus extract. However, it was observed that retinol exhibited dose-dependent inhibition of TBE cell growth when EGF was removed from this serum-free culture condition. This inhibition can be reversed if EGF or the conditioned medium of primary TBE cells that are maintained in vitamin A-deficient condition is added. This type of EGF-retinol interacting phenomenon was not observed with the 5 remaining hormonal supplements. Analysis of ¹²⁵I-labeled EGF binding shows a down-regulation of the high affinity binding sites (K_d = 0.09 n^m) on TBE cells grown in the absence of vitamin A. These results suggest that TBE cells are capable of secreting an EGF-like growth factor in the absence of vitamin A. The possibility that transforming growth factor- (TGF-) is involved in this phenomenon is further examined by antibodies specific to TGF- and its binding to an EGF-receptor. Using the TGF- antibody, the presence of a TGF--specific antigen was found to be 3-fold higher in the conditioned medium obtained from the vitamin A-deficient cultures than that derived from retinol-treated cultures. Furthermore, the antibody neutralizing the TGF- binding to an EGF receptor was able to reduce the DNA synthesis associated with the vitamin A deficiency. These results suggest that vitamin A plays an important regulatory role in the paracrine/autocrine secretion of EGF/TGF--like mitogen in TBE cell cultures.

¹ Supported by grants from the NIH (HL35635, ES00628), the Council for Tobacco Research, Inc. (Grant 2611), and the California Tobacco-Related Disease Research Program (RT-0409).

² Present address: Department of Histology & Embryology. Shanghai Medical School, Shanghai, 200032, People's Republic of China.

³ To whom requests for reprints should be addressed, at California Regional Primate Research Center, University of California at Davis, Davis, CA 95616.

Received 12/23/92. Accepted 3/23/93.

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