Studies on the pathophysiology of reflux esophagitis have focused on the associated motility and/or structural abnormalities, with relatively little attention directed to inflammatory mediators involved in the acid-induced mucosal injury. Mast cells line the subepithelial lamina propria in both humans and the opossum model, and are ideally positioned to respond to luminal agents that cross the mucosal barrier. To determine whether certain mast cell mediators are involved in acid-induced mucosal injury, epithelial injury scores following 60 min of luminal perfusion of the opossum esophagus with 100 mM HCl were compared in the presence and absence of two different mast cell stabilizers (disodium cromoglycate and doxantrazole) or the selective platelet-activating factor antagonist TCV-309. In control animals acid perfusion caused release of PAF and significant epithelial injury, characterized by epithelial sloughing and cleft formation. This injury was unaffected by pretreatment with disodium cromoglycate or doxantrazole but was completely prevented by TCV-309 (histology damage score, 2.40+/-0.28 in controls vs 0.50 +/- 0.14 in TCV-309-treated animals). These studies suggest that platelet-activating factor is an important mediator of acid-induced esophageal mucosal damage.