Respiratory epithelia are one of vitamin A-targeted tissues. In vitamin A deficiency, the epithelium changes to squamous keratinizing one. This phenomenon is called """"""""squamous metaplasia"""""""". This lesion can be produced also by treatment with various toxic agents, including carcinogens. The importance of this lesion has been recognized in the development of bronchogenic cancer. In this proposal, we propose a hypothesis of autocrine regulation mechanism in the development of this lesion. It is proposed that epithelial cells during vitamin A deficiency produce growth factor and cells then use this factor for their continuous proliferation. Normally, vitamin A controls negatively the production of this cell-derived growth factor. In my laboratory, we have developed a serum-free, hormone-supplemented medium for continuous proliferation of human bronchial epithelial (HBE) cells in vitro. Properties of cultured HBE cells resemble to those of squamous metaplastic epithelia in many aspects; such as secretion of hyaluronate, formation of tonofilaments. Growth of cultured HBE cells is also under the vitamin A control. In the absence of vitamin A, cells secrete growth factor which can overcome the growth inhibition of vitamin A under a specific condition. This phenomenon is similar to that occurs in vivo during squamous metaplasia. Therefore, the culture system developed in this study can be used as an in vitro model to test the hypothesis and to elucidate the nature of this squamous phenomenon. We propose to isolate this cell-derived growth factor and to elucidate the chemical nature of this molecule. We would like to generate antibodies and cDNA corresponding to this growth factor. Both of them will be used in studies to elucidate roles of vitamin A and this growth factor in epithelial cell growth. These studies will be able to evaluate the potential role of """"""""autocrine secretion"""""""" in this classic """"""""squamous metaplasia"""""""" of respiratory epithelium.
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