Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis.
OBJECTIVE
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 epithelial 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 micromol/L, 2 hours), platelet activating factor (PAF), prostaglandin E2 (PGE2), and F2-isoprostane increased 2.5, 5.2, and 36 times, respectively. In E-LES, levels of PAF, PGE2, and F2-isoprostane were 4, 6, and 40 times, respectively, higher than in N-LES. PAF, PGE2, and F2 isoprostane produced dose-dependent reductions in tone of N-LES muscle strips.


CONCLUSIONS
We conclude that an excessive production of H2O2 triggers an increased production of PAF, PGE2, and F2-isoprostane, which are responsible for reducing LES tone in human esophagitis.
Cheng
Ling
L
Division of Gastroenterology, Rhode Island Hospital and Brown University, Providence, Rhode Island 02903, USA. piero_biancani@brown.edu
Harnett
Karen M
KM
Cao
Weibiao
W
Liu
Fang
F
Behar
Jose
J
Fiocchi
Claudio
C
Biancani
Piero
P
D015237:Dinoprost / Q000378:metabolism; D049630:Esophageal Sphincter, Lower / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004942:Esophagitis, Peptic / Q000378:metabolism / Q000503:physiopathology*; D028441:F2-Isoprostanes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D009129:Muscle Tonus / Q000187:drug effects*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D028441:F2-Isoprostanes; D018836:Inflammation Mediators; D016877:Oxidants; D010972:Platelet Activating Factor; D015237:Dinoprost; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D010100:Oxygen