ULCER-INDUCED ALTERATIONS IN CELL PHENOTYPE AND MATRIX AND GROWTH-FACTOR EXPRESSION

Objectives: To characterize the changes in enterocyte phenotype, expre ssion of growth factors and matrix proteins in healing ulcers. Design: Specific antibodies were used to assess growth factor and matrix expr ession in duodenal and gastric ulcers in rats. Methods: Perforating du odenal ulcers were modeled in Sprague-Dawley rats by surgical creation of a transmural defect which was sealed by omentopexy. In comparative studies, gastric mucosal ulcerations were created with a cryoprobe. A fter the rats were killed, the ulcer bed was evaluated histologically and by immunofluorescent staining for growth factors, matrix proteins and integrins. In situ hybridization was used to study trefoil growth factor messenger (m)RNA expression. Results: Omental plugging of the d uodenal defect was observed, with infiltration of inflammatory cells. Partial re-epithelialization by mucosal enterocytes had occurred 2 day s after the injury, with concomitant reconstitution of basement membra ne and interstitial matrix proteins below the neomucosa. Immunofluores cent staining demonstrated substantial platelet-derived growth factor immunoreactivity in endothelial cells along the lamina propria. The tr efoil growth factors, in particular spasmolytic peptide and intestinal trefoil factor, were evident in duodenal mucosal Brunner's glands, wh ile intestinal trefoil factor was observed in duodenal goblet cells. T hese factors did not change significantly after duodenal transmural in jury except for an increased amount of intestinal trefoil factor in du odenal endocrine cells adjacent to the defect. Ectopic expression of i ntestinal trefoil factor and ribosomal spasmolytic peptide message and protein was upregulated within the gastric mucosa after cryoprobe inj ury. Complementary investigations of human gastric ulcers demonstrated upregulation of human spasmolytic peptide and pS2 also. Conclusions: Modulation of the mucosal enterocyte phenotype and of the expression o f growth factors and extracellular matrix proteins was demonstrable in two models of ulcer healing in the rat, the transmural duodenal defec t with omentopexy and the gastric cryoprobe wound. The precise contrib ution from the omentum was not specifically defined. These systems rep resent viable models for studies on the cell biology of ulcer healing and for validation of data from in vitro studies in cultured cells.