Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability

Abstract

There are several pathophysiologic conditions in which intestinal inflammation is associated with enhanced mucosal permeability, fluid loss, and epithelial cell injury. The objective of this study was to determine the effects of polymorphonuclear leukocyte (PMN)-derived oxidants on ileal mucosal permeability in vivo as well as electrolyte transport and epithelial cell viability in vitro. Using blood-to-lumen clearance of [51Cr]EDTA as a measure of mucosal permeability, we found that luminal perfusion with hydrogen peroxide (H2O2), hypochlorous acid (HOCl), or monochloramine (NH2Cl) produced a dose-dependent increase in mucosal permeability. Perfusion with 0.1 mM, 0.5 mM, and 1.0 mM oxidant produced a 2 +/- 1, 5 +/- 2, and 11 +/- 5-fold increase in mucosal permeability for H2O2, a 2 +/- 1, 8 +/- 3, and 36 +/- 12-fold increase for HOCl, and a 3 +/- 1, 11 +/- 2, and 30 +/- 7-fold increase for NH2Cl. Taurine monochloramine (TauNHCl) was ineffective in enhancing the blood-to-lumen clearance of [51Cr]EDTA. Furthermore, 0.01 mM and 0.1 mM NH2Cl and H2O2 produced significant increases in short-circuit current across rat ileum in vitro, whereas HOCl and TauNHCl were without effect. Tissue resistance and potential difference were not altered, suggesting that NH2Cl, HOCl, and H2O2 were not cytotoxic under these conditions. Cultured intestinal epithelial cells exposed to NH2Cl and HOCl were injured in a dose-dependent manner in vitro, whereas H2O2 and Tau NHCl were nontoxic. Taken together, our data suggest that PMN-derived oxidants may mediate the enhanced mucosal permeability, electrolyte transport, and epithelial cell injury associated with acute inflammation of the bowel.