RT Journal Article SR Electronic T1 Acid-Induced Release of Platelet-Activating Factor by Human Esophageal Mucosa Induces Inflammatory Mediators in Circular Smooth Muscle JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 117 OP 126 DO 10.1124/jpet.106.106104 VO 319 IS 1 A1 Cheng, Ling A1 Cao, Weibiao A1 Behar, Jose A1 Fiocchi, Claudio A1 Biancani, Piero A1 Harnett, Karen M. YR 2006 UL http://jpet.aspetjournals.org/content/319/1/117.abstract AB 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 of 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 electrical field stimulation (EFS), but supernatant of HCl-treated mucosa abolished contraction. The inhibition was reversed by the platelet-activating factor (PAF) antagonist CV3988 [(±)-3-(N-octadecylcarbamoyl)-2-methoxy) propyl-(2-thiazolioethyl) phosphate], whereas the PAF analog 2-O-methyl platelet-activating factor C-16 (PAF-16) inhibited EFS-induced contraction and acetylcholine (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 hydrogen peroxide (H2O2) in mucosa, mucosa supernatant, and circular muscle. HCl increased PAF and interleukin (IL)-1β (but not IL-6, prostaglandin E2, 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-1β, 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. The American Society for Pharmacology and Experimental Therapeutics