Vol. 286, Issue 1, 469-480, July 1998

Paracrine Endothelin Signaling in the Control of Basal Cell Proliferation in Guinea Pig Tracheal Epithelium

Haruaki Ninomiya, Takashi Inui and Tomoh Masaki

Department of Pharmacology, Faculty of Medicine, Kyoto University (H.N., T.M.), Kyoto 606 and Takarazuka Research Institute (T.I.), Novartis Pharma K. K., Takarazuka 665, Japan

Immunofluorescent analyses revealed distinct cellular/subcellular localization of endothelin (ET) receptors and ET-1 in the epithelial cell layer of guinea pig trachea. ETA was expressed predominantly in the basal cells. ETB was expressed predominantly in the ciliated columnar cells and was polarized at the apical side of the cell body within the cells. Anti-ET-1-immunoreactive cytoplasmic granules were contained in the secretory cells that were scattered throughout the epithelial layer. Cell proliferation assays with immersion cultures of differentially plated cells (basal cell-enriched, non-basal cell-enriched and mixed cell cultures) indicated the presence of paracrine ET-1 signaling pathways that transmit both positive and negative effects on the basal cell proliferation. Direct activation of ETA expressed on the basal cells caused enhancement of their growth, whereas that of ETB expressed on the ciliated columnar cells caused suppression of the basal cell growth. The latter effect was transmitted by nitric oxide whose production was stimulated by ETB activation. Furthermore, blockade of either ETA or ETB compromised the epithelial cell layer formation under the air-interphase culture, which indicates the dependence of tracheal epithelial remodeling on a balance between the positive and negative effects of ET-1 on the basal cell growth.