During injury to the gastric mucosa, lysosomes become more fragile and lysosomal enzymes, which are activated at acid pH, leak into the surrounding environment. It is not clear whether these changes contribute to the mechanism of damage or are merely a secondary result of it. To test whether lysosomes modulate gastric mucosal damage, we pretreated rats with a lysosomal labilizing agent, Triton WR 1339 (1.5 g/kg) and histologically assessed mucosal damage in vivo after challenge with 30% ethanol. No significant differences were found in the length or depth of eroded mucosa: mean erosion length, Triton 23.9 +/- 6.6% vs. control 19.7 +/- 5.2%; mean depth (micron), Triton 19 +/- 4 vs. control 20 +/- 7. After a similar pretreatment regimen, rat antral mucosa was cultured, challenged with ethanol and damage assessed by release into media of previously incorporated mucosal 51chromium. With 15% ethanol challenge, no change in 51chromium release was seen: after Triton, 9.8 +/- 1.4% vs. control 10.3 +/- 1.0%. Triton pretreatment perturbed gastric lysosomes as shown in organ culture by significantly raised tissue lysosomal enzyme activities and increased lysosomal enzyme release into culture media after ethanol challenge. The lack of effect of this pretreatment regimen suggests that lysosomes do not have a major pathogenetic role in ethanol-induced gastric damage.