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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Acid-Induced Release of Platelet-Activating Factor by Human Esophageal Mucosa Induces Inflammatory Mediators in Circular Smooth Muscle

Division of Gastroenterology, Rhode Island Hospital and Brown University, Providence, Rhode Island (L.C., W.C., J.B., P.B., K.M.H.); and Division of Gastroenterology, Case Western Reserve University, Cleveland, Ohio (C.F.)

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)-1 (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-1, 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.

Address correspondence to: Dr. Karen M. Harnett, Rhode Island Hospital Gastrointestinal Motor Function Research Laboratory, 55 Claverick Street, Room 333, Providence, RI 02903. E-mail: karen_harnett{at}brown.edu

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