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NEUROREGULATION AND MOTILITY

HCl-induced inflammatory mediators in cat esophageal mucosa and inflammatory mediators in esophageal circular muscle in an in vitro model of esophagitis

¹Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island; and ²Department of Pathobiology, Lerner Research Institute and ³Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation University, Cleveland, Ohio

Submitted 20 December 2005 ; accepted in final form 19 January 2006

Platelet-activating factor (PAF) and interleukin-6 (IL-6) are produced in the esophagus in response to HCl and affect ACh release, causing changes in esophageal motor function similar to esophagitis (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G418–G428, 2005). We therefore examined HCl-activated mechanisms for production of PAF and IL-6 in cat esophageal mucosa and circular muscle. A segment of normal mucosa was tied at both ends, forming a mucosal sac (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G860–G869, 2005) that was filled with acidic Krebs buffer (pH 5.8) or normal Krebs buffer (pH 7.0) as control and kept in oxygenated Krebs buffer for 3 h. The supernatant of the acidic sac (MS-HCl) abolished contraction of normal muscle strips in response to electric field stimulation. The inhibition was reversed by the PAF antagonist CV3988 and by IL-6 antibodies. PAF and IL-6 levels in MS-HCl and mucosa were significantly elevated over control. IL-6 levels in mucosa and supernatant were reduced by CV3988, suggesting that formation of IL-6 depends on PAF. PAF-receptor mRNA levels were not detected by RT-PCR in normal mucosa, but were significantly elevated after exposure to HCl, indicating that HCl causes production of PAF and expression of PAF receptors in esophageal mucosa and that PAF causes production of IL-6. PAF and IL-6, produced in the mucosa, are released to affect the circular muscle layer. In the circular muscle, PAF causes production of additional IL-6 that activates NADPH oxidase to induce production of H₂O₂. H₂O₂ causes formation of IL-1 that may induce production of PAF in the muscle, possibly closing a self-sustaining cycle of production of inflammatory mediators.

inflammation; smooth muscle contraction; reactive oxygen species; cytokines

This article has been cited by other articles:

				W. Cao, L. Cheng, J. Behar, P. Biancani, and K. M. Harnett IL-1beta signaling in cat lower esophageal sphincter circular muscle Am J Physiol Gastrointest Liver Physiol, October 1, 2006; 291(4): G672 - G680. [Abstract] [Full Text] [PDF]