GASTROENTEROLOGY 1992;102:1467-1474 Increased Production of Transforming Growth Factor a Following Acute Gastric Injury WILLIAM H. POLK, Jr., PETER J. DEMPSEY, WILLIAM E. RUSSELL, PAMELA I. BROWN, R. DANIEL BEAUCHAMP, JOHN A. BARNARD, and ROBERT J, COFFEY, Jr. Departments of Surgery, Medicine, Pediatrics, and Cell Biology, Vanderbilt University, Nashville, Tennessee; Department of Surgery, University of Texas Medical Branch, Galveston, Texas; and Children’s Service, Massachusetts General Hospital, Boston, Massachusetts Transforming growth factor a (TGF-a) production recently has been found in normal mammalian gas- tric mucosa. Inasmuch as TGF-a and epidermal growth factor (EGF) both stimulate epithelial cell migration and proliferation and suppress gastric acid secretion, the authors of the current study pro- posed that these growth factors may participate in tissue repair after acute gastric mucosal injury. Consequently, TGF-a and EGF production were ex- amined after orogastric administration of either acidified taurocholate or 0.6 mol/L HCl to rats. TGF-a messenger RNA (mRNA) expression in- creased in a dose- and time-dependent manner after administration of taurocholate, whereas EGF mRNA expression was not detected. Radioimmuno- assay of gastric mucosal scrapings obtained 6 hours after gastric injury induced by 0.6 mol/L HCl showed a 2.1-fold increase in immunoreactive TGF-a hut no increase in immunoreactive EGF. In addition, there was a 68-fold increase in immunore- active TGF-a in gastric juice within 30 minutes of gastric instillation of HCl and, again, no increase in immunoreactive EGF. There is a rapid appearance of TGF-a in the gastric juice within 30 minutes of injury, which is followed by increased expression of TGF-a mRNA and protein in the gastric mucosa. These studies suggest that locally produced TGF-a may participate in gastric mucosal repair following acute gastric injury to rats. T he reparative events following acute gastric mu- cosal injury have been studied extensively us- ing many in vitro and in vivo models.14 Repair of superficial epithelial cell loss, a process that is de- pendent on cell migration, begins within 5 minutes of acute injury and is nearly complete within 1 hour. Deeper mucosal erosions may persist for 5 days after acute injury and require DNA synthesis for repair.’ A variety of factors may contribute to repair of acute gastric mucosal injury. Prostaglandins may limit the initial injury to the mucosa and lamina pro- pria6 but are not required for epithelial cell migra- tion.2 An intact lamina propria with injury limited to the superficial mucosa is a likely prerequisite for rapid early epithelial repair,’ suggesting that the epi- thelium interacts with factors in the underlying con- nective tissue stroma. The presence of a “ mucoid cap” promotes restitution, probably by protecting the lamina propria from luminal acid, thus limiting the extent of the initial injury.’ Epidermal growth factor (EGF) has been consid- ered an attractive candidate to participate in gastric repair, because it is acid stable,g stimulates epithelial cell migration” and DNA synthesis,“-‘3 suppresses acid production,‘4-16 and stimulates gastric mucus production.17*le EGF is a X&amino acid polypeptidelg that is produced in the submandibular gland, Brun- ner’s glands of the duodenum, and the distal tubule of the kidney.” EGF messenger RNA (mRNA) ex- pression is not detected in normal adult human gas- tric mucosa,21 but EGF is produced in the salivary glands and delivered to the stomach in saliva. The EGF receptor is found in normal adult gastric mu- cosa.22 The hypothesis that EGF participates in the repair of gastric mucosal injury is suggested by stud- ies in sialoadenectomized rats. These rats have atro- phic gastric mucosa23 and delayed healing of gastric and duodenal ulceration that is reversed by oral or parenteral EGF.24 Transforming growth factor a (TGF-a) is an acid- stable protein that shares 35% sequence homology, a common receptor (EGFr), and a nearly identical spectrum of biological activities2’ with EGF. TGF-a exists in the mature form as a 50-amino acid poly- peptide. Recently, TGF-(x. mRNA expression and pro- tein production were shown in normal gastric mu- cosa.21,26 Similar to EGF, TGF-a suppresses acid 0 1992 by the American Gastroenterological Association 0016-5065/92/$3.00