Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis

Background& Aims: We have previously used the normal lower esophageal sphincter (N-LES) of human organ donors to examine the physiologic signal transduction of lower esophageal sphincter (LES) circular muscle. Now, for the first time, we have obtained a human LES specimen with esophagitis (E-LES) and characterized its pathophysiologic mechanical and inflammatory profiles. Methods: E-LES was examined histologically, and its in vitro circular muscle contraction and production of inflammatory mediators were compared with those of N-LES. Results: E-LES exhibited scattered erosions and displayed inflammatory cells in the epithelia[ layer, basal zone hyperplasia, and elongation of lamina propria papillae, characteristic of chronic reflux esophagitis. E-LES muscle strips developed lower in vitro tone (0.78 g) than N-LES (3.3 +/- 0.2 g). E-LES tone was essentially restored to normal by the H2O2 scavenger catalase, suggesting that H2O2 was responsible for reduction of tone. NOX5 cDNA was higher and H2O2 levels were 4 times higher in E-LES circular muscle (0.85 nmol/mg protein) than in N-LES (0.19 +/- 0.05 nmol/mg protein). When N-LES smooth muscle was incubated in H2O2 (70 mu mol/L, 2 hours), platelet activating factor (PAF), prostaglandin E-2 (PGE(2)), and F-2-isoprostane increased 2.5, 5.2, and 36 times, respectively. In E-LES, levels of PAF, PGE(2), and F-2-isoprostane were 4, 6, and 40 times, respectively, higher than in N-LES. PAF, PGE(2), and F-2 isoprostane produced dose-dependent reductions in tone of WILES muscle strips. Conclusions: We conclude that an excessive production of H2O2 triggers an increased production of PAF, PGE(2), and F-2-isoprostane, which are responsible for reducing LES tone in human esophagitis.