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

Abstract

Myogenic lower esophageal sphincter (LES) tone is maintained by arachidonic acid metabolites, such as PGF2αand thromboxane A2/B2. Experimental esophagitis in cat reduces LES in vivo pressure and in vitro tone. Because IL-1β may mediate esophagitis-associated reduction in ACh release in esophagus, we examined whether IL-1β 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-1β levels were higher in esophagitis than in normal LES. IL-1β reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H2O2. This was confirmed by IL-1β-induced production of H2O2in normal LES and elevated H2O2levels in esophagitis. H2O2by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H2O2increased PGE2in normal LES, and PGE2levels were elevated in esophagitis LES, whereas PGF2αlevels were unchanged. H2O2also 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 PGF2αanalog 8-iso-PGF2αcaused little contraction of LES strips but reduced PGF2αbinding and contraction of normal LES. In esophagitis, PGF2αbinding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1β causes production of H2O2. H2O2increases PGE2, which relaxes the LES, and 8-iso-F2α, which blocks PGF2α-mediated contraction.