TGF-alpha inhibits gastric acid secretion and may play an important role in epithelial repair. We quantitated regional levels of TGF-alpha in the human proximal gastrointestinal tract and determined whether they are affected by acid suppression or aspirin-induced injury. Ten healthy volunteers were studied. After baseline endoscopy with biopsy, five randomly received no treatment, aspirin, omeprazole, or cimetidine for one week. Endoscopy was repeated and prior unhealed biopsy sites quantitated. TGF-alpha levels were measured by RIA. Five additional subjects then completed an extended protocol of three weeks duration. All subjects were free of H. pylori infection. TGF-alpha levels in the antrum, 34.76 +/- 5.54 pg TGF-alpha/micrograms DNA were threefold higher than in the gastric body and duodenum (11.03 +/- 2.60 and 10.41 +/- 1.64 respectively, P < 0.01). The number of unhealed sites in the aspirin group was significantly greater than in the control or acid inhibition groups; however, TGF-alpha levels were not different from-the surrounding mucosa. TGF-alpha increased in the controls after biopsy; the increase was significant in the body at week 2 only. Aspirin significantly increased TGF-alpha levels in the gastric body and duodenum after one week. The rise in antral TGF-alpha appeared delayed and blunted by the aspirin treatment compared to control. There was no relationship between the number of visible biopsy sites, degree of aspirin-induced injury, and the TGF-alpha level. Acid suppression was associated with a significant increase in TGF-alpha in the gastric body and antrum at one week. Immunochemical staining did not demonstrate differences in proliferation in any treatment group compared to controls. TGF-alpha levels vary by location in the proximal gastrointestinal tract, with significantly greater levels in the antrum. After biopsy, TGF-alpha levels increase; short-term aspirin and acid inhibitors modulate this effect. Aspirin significantly impaired the healing of endoscopic biopsies in the antrum; however, this was not associated with changes in TGF-alpha levels. TGF-alpha levels did not change in response to acid secretory state. Further studies of mucosal levels of TGF-alpha in response to aspirin-induced injury in humans appear warranted.