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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 28, 2006; DOI: 10.1124/jpet.106.106104

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Received for publication April 19, 2006.
Revised June 1, 2006.
Accepted for publication June 27, 2006.

ACID INDUCED RELEASE OF PAF BY HUMAN ESOPHAGEAL MUCOSA INDUCES INFLAMMATORY MEDIATORS IN CIRCULAR SMOOTH MUSCLE

Ling Cheng 1, Weibiao Cao 1, Jose Behar 1, Claudio Fiocchi 2, Piero Biancani 3, Karen M. Harnett 3*

1 Brown Medical School & Rhode Island Hospital 2 Case Western Reserve University 3 Brown University & Rhode Island Hospital

* Address correspondence to: E-mail: karen_harnett{at}brown.edu

Abstract

In a human in vitro model of esophagitis we investigated the genesis of esophagitis-associated dysmotility by examining HCl-induced production of inflammatory mediators in the mucosa, and investigating their effect on esophageal circular muscle. Muscularis propria was removed from organ donors' esophagi, leaving the mucosal tube intact. The tube was tied at both ends, forming a sac, and filled with HCl, at pH 4. After 3 h incubation the supernatant surrounding the sac was analyzed, or applied to circular muscle strips. HCl alone did not affect circular muscle contraction in response to EFS, but supernatant of HCl-treated mucosa abolished contraction. The inhibition was reversed by the PAF antagonist CV3988, whereas the PAF analog PAF16 inhibited EFS-induced contraction and ACh release in circular muscle strips. The hydrogen peroxide scavenger catalase reversed the inhibition in contraction, to the same extent as CV3988. We therefore measured PAF and H2O2 in mucosa, mucosa supernatant and circular muscle. HCl increased PAF and IL-1{beta} (but not IL-6, PGE2 or H2O2) in mucosa and only PAF was released into the supernatant, presumably to affect circular muscle. In circular muscle exogenous PAF induced sequential formation of IL-6, H2O2, IL-1{beta} and PAF. Release of PAF by the mucosa inhibits ACh release from circular muscle layer neurons and initiates sequential formation of inflammatory mediators in muscle, resulting in production of PAF by the muscle itself, possibly initiating in a self-sustaining cycle.


Key words: NADPH oxidase, cytokines, esophageal motor function, inflammation, reactive oxygen species, smooth muscle contraction


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