Esophageal ulceration activates keratinocyte growth factor and its receptor in rats: Implications for ulcer healing

Background & Aims: Cellular and molecular mechanisms of esophageal ulcer healing remain unexplored. We studied the sequential cellular events and the expression of keratinocyte growth factor (KGF) and its receptor (KGF-R) during the healing of experimental esophageal ulcers. Methods: Esophageal ulcers were produced in rats by local application of acetic acid. Studies included (1) ulcer size, (2) quantitative histology, and (3) KGF and KGF-R messenger RNA and protein expression by reverse-transcription polymerase chain reaction, Western blotting, and immunostaining. In separate groups, ulcer size and esophageal epithelial proliferation were evaluated after a single injection of recombinant human KGF (1 mg/kg) around the ulcer. Results. Ulcers were fully developed 3 days after induction, and 58% of ulcers were re-epithelialized by 9 days. At 3 days, in esophageal tissue bordering the ulcers, KGF messenger RNA and protein were increased by 191% and 151%, respectively, and KGF-R messenger RNA and protein were increased by 357% and 237%, respectively. KGF was expressed in stromal cells, whereas KGF-R was expressed in epithelial cells. At 6 days, epithelial proliferation at the ulcer margin was increased by 216%, and treatment with KGF further enhanced cell proliferation and accelerated ulcer healing. Conclusions: KGF is a likely mediator of esophageal epithelial proliferation and ulcer healing.