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The LES separates
the stomach from the esophagus and prevents reflux of gastric
acid into the esophagus by maintaining a sustained tonic contraction.
Our laboratory has recently discovered that maintenance of
tone depends on arachidonic acid metabolism, resulting in
production of prostaglandin (PG) F2alpha and thromboxane A2,
which contract LES smooth muscle. Gastroesophageal reflux
disease is associated with a reduction in LES tone, which
may arise from inflammatory mediators released by immune cells
in response to acid-induced inflammation and cell damage.
Relevant inflammatory mediators may be H2O2 and the inflammatory
cytokine interleukin 1beta. H2O2 causes depletion of intracellular
Ca2+ stores, and increases production of PGE2, which relaxes
LES smooth muscle. In addition, H2O2 and other oxygen radicals
may directly oxygenate membrane phospholipids, resulting in
non-enzymatic formation of stable PG analogs, such as F2 isoprostane,
which act as weak agonists/antagonists at PGF2alpha receptors,
decreasing the effectiveness of endogenous PGF2alpha.
Interleukin 1beta
contributes to formation of the relaxant prostaglandin PGE2,
either directly or indirectly, by inducing formation of H2O2.
These data suggest that the reduction in LES tone associated
with gastroesophageal reflux disease may result from a shift
in the production of arachidonic acid metabolites secondary
to exposure to inflammatory mediators. Our research is presently
investigating the mechanisms responsible for this shift in
arachidonic acid metabolism.
Selected
Publications:
Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, Harnett KM. HCl-Induced Inflammatory Mediators in Cat Esophageal Mucosa and Inflammatory Mediators in Esophageal Circular Muscle in an In Vitro Model of Esophagitis. Am J Physiol Gastrointest Liver Physiol. . Epub 2006 Jan 26.
Cheng L, Harnett KM, Cao W, Liu F, Behar J, Fiocchi C, Biancani P. Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis. Gastroenterology. 2005 Nov;129(5):1675-85.
Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, Harnett KM. In vitro model of acute esophagitis in the cat. Am J Physiol Gastrointest Liver Physiol. 2005 Nov;289(5):G860-9. Epub 2005 Jul 21.
Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, Harnett KM. Platelet-activating factor and prostaglandin E2 impair esophageal ACh release in experimental esophagitis. Am J Physiol Gastrointest Liver Physiol. 2005 Sep;289(3):G418-28. Epub 2005 May 12.
Harnett KM, Cao W, Biancani P. Signal-transduction pathways that regulate smooth muscle function I. Signal transduction in phasic (esophageal) and tonic (gastroesophageal sphincter) smooth muscles. Am J Physiol Gastrointest Liver Physiol. 2005 Mar;288(3):G407-16.
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