Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Myogenic lower esophageal sphincter (LES) tone is maintained by arachidonic acid metabolites, such as PGF(2 alpha) and thromboxane A(2)/B-2. Experimental esophagitis in cat reduces LES in vivo pressure and in vitro tone. Because IL-1 beta may mediate esophagitis-associated reduction in ACh release in esophagus, we examined whether IL-1 beta may also play a role in esophagitis- induced reduction of LES tone. A cat model of experimental esophagitis was obtained by repeated esophageal perfusion with HCl (Biancani P, Barwick K, Selling J, and McCallum R. Gastreonterology 87: 8 - 16, 1984 and Sohn UD, Harnett KM, Cao W, Rich H, Kim N, Behar J, and Biancani P. J Pharmacol Exp Ther 283: 1293 - 1304, 1997.). LES circular muscle strips were examined in muscle chambers as previously described ( Biancani P, Billett G, Hillemeier C, Nissenshon M, Rhim BY, Sweczack S, and Behar J. Gastroenterology 103: 1199 - 1206, 1992). Levels of inflammatory mediators were measured. IL-1 beta levels were higher in esophagitis than in normal LES. IL-1 beta reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H2O2. This was confirmed by IL-1 beta-induced production of H2O2 in normal LES and elevated H2O2 levels in esophagitis. H2O2 by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H2O2 increased PGE(2) in normal LES, and PGE(2) levels were elevated in esophagitis LES, whereas PGF(2 alpha) levels were unchanged. H2O2 also increased levels of 8-isoprostanes, stable prostaglandin-like compounds formed by free radical-induced peroxidation of arachidonic acid, and 8-isoprostane levels were elevated in esophagitis. The PGF(2 alpha) analog 8-iso-PGF(2 alpha) caused little contraction of LES strips but reduced PGF(2 alpha) binding and contraction of normal LES. In esophagitis, PGF(2 alpha) binding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1 beta causes production of H2O2. H2O2 increases PGE(2), which relaxes the LES, and 8-iso-F-2 alpha, which blocks PGF(2 alpha)-mediated contraction.