HEPATOCYTE GROWTH FACTOR SCATTER FACTOR EFFECTS ON EPITHELIA - REGULATION OF INTERCELLULAR-JUNCTIONS IN TRANSFORMED AND NONTRANSFORMED CELL-LINES, BASOLATERAL POLARIZATION OF C-MET RECEPTOR IN TRANSFORMED AND NATURAL INTESTINAL EPITHELIA, AND INDUCTION OF RAPID WOUND REPAIR IN ATRANSFORMED MODEL EPITHELIUM/

Intestinal epithelial cells rest on a fibroblast sheath. Thus, factors produced by these fibroblasts may influence epithelial function in a paracrine fashion. We examined modulation of intestinal epithelial fun ction by one such fibroblast product, scatter factor/hepatocyte growth factor (HGF/SF). This effect was studied in vitro by using model T84 intestinal epithelial cells. When applied to confluent T84 monolayers, HGF/SF attenuates transepithelial resistance to passive ion flow in a dose-dependent manner(maximum fall at 300 ng/ml, 28% control monolaye r resistance, P < 0.001, ED(50) of 1.2 nM), t(1/2) of 20 h. This funct ional effect of HGF/SF and distribution of its receptor, c-met, are po larized to the basolateral membranes of T84 intestinal epithelial cell s. HGF/SF effects on resistance are not attributable to altered transc ellular resistance (opening of Cl- and/or basolateral K+ channels), cy totoxicity, or enhanced cell proliferation; they therefore represent s pecific regulation of paracellular tight junction resistance. Analysis with biochemically purified rodent HGF/SF and Madin-Darby canine kidn ey cells reveals that effects on paracellular tight junctions also occ ur in other nontransformed epithelia. Binding of HGF/SF to its recepto r in T84 intestinal epithelial cells is accompanied by tyrosine phosph orylation of the receptor. Because loosening of intercellular junction s between cells could facilitate separation, spreading, and migration of epithelial cells during physiologic processes such as wound reseali ng, we determined the effects of HGF/SF on intestinal epithelial wound resealing using our previously published in vitro model (Nusrat, A., C. Delp, and J. L. Madara. 1992. J. Clin. Invest. 89:1501-1511). HGF/S F markedly enhanced wound closure (> 450% increase in rate, P < 0.001) by influencing the migratory and spreading response in not only cells adjoining the wound but also cells many positions removed from the wo und. We thus speculate that HGF/SF may serve as an important cytokine that influences epithelial parameters such as transepithelial resistan ce and wound resealing. Further pharmacological approaches to manipula te HGF/SF signaling pathways may provide novel therapeutic strategies to enhance repair of intestinal epithelial erosions/ulcerations.