Advanced oxidation protein products induce intestine epithelial cell death through a redox-dependent, c-jun N-terminal kinase and poly (ADP-ribose) polymerase-1-mediated pathway

F Xie,S Sun,S Zheng,P Wu,A Xu,J H Zeng,L Bai,M Xue

doi:10.1038/cddis.2013.542

Abstract

Advanced oxidation protein products (AOPPs), a novel protein marker of oxidative damage, have been confirmed to accumulate in patients with inflammatory bowel disease (IBD), as well as those with diabetes and chronic kidney disease. However, the role of AOPPs in the intestinal epithelium remains unclear. This study was designed to investigate whether AOPPs have an effect on intestinal epithelial cell (IEC) death and intestinal injury. Immortalized rat intestinal epithelial (IEC-6) cells and normal Sprague Dawley rats were treated with AOPP-albumin prepared by incubation of rat serum albumin (RSA) with hypochlorous acid. Epithelial cell death, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit activity, reactive oxygen species (ROS) generation, apoptosis-related protein expression, and c-jun N-terminal kinase (JNK) phosphorylation were detected both in vivo and in vitro. In addition, we measured AOPPs deposition and IEC death in 23 subjects with Crohn's disease (CD). Extracellular AOPP-RSA accumulation induced apoptosis in IEC-6 cultures. The triggering effect of AOPPs was mainly mediated by a redox-dependent pathway, including NADPH oxidase-derived ROS generation, JNK phosphorylation, and poly (ADP-ribose) polymerase-1 (PARP-1) activation. Chronic AOPP-RSA administration to normal rats resulted in AOPPs deposition in the villous epithelial cells and in inflammatory cells in the lamina propria. These changes were companied with IEC death, inflammatory cellular infiltration, and intestinal injury. Both cell death and intestinal injury were ameliorated by chronic treatment with apocynin. Furthermore, AOPPs deposition was also observed in IECs and inflammatory cells in the lamina propria of patients with CD. The high immunoreactive score of AOPPs showed increased apoptosis. Our results demonstrate that AOPPs trigger IEC death and intestinal tissue injury via a redox-mediated pathway. These data suggest that AOPPs may represent a novel pathogenic factor that contributes to IBD progression. Targeting AOPP-induced cellular mechanisms might emerge as a promising therapeutic option for patients with IBD.

Highlights

Increased plasma advanced oxidation protein products (AOPPs) formation has been reported in patients with chronic kidney disease,[5] diabetes,[7] and chronic hepatitis C.8 As a novel protein marker of oxidant-mediated protein damage, AOPPs participate in these pathophysiologic conditions
To evaluate whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidases were responsible for intracellular reactive oxygen species (ROS) generation, the experiment was repeated with the NADPH oxidase inhibitors diphenylene iodinium (DPI) and apocynin
We present in vitro and in vivo lines of evidence that AOPPs induced Intestinal epithelial cells (IECs) death via a redox-dependent, jun N-terminal kinase (JNK)- and poly (ADP-ribose) polymerase-1 (PARP-1)-mediated

Summary

Introduction

Increased plasma AOPP formation has been reported in patients with chronic kidney disease,[5] diabetes,[7] and chronic hepatitis C.8 As a novel protein marker of oxidant-mediated protein damage, AOPPs participate in these pathophysiologic conditions. There is a growing body of literature showing that excessive cell death is associated with chronic inflammation, as seen in patients with IBD, and this could contribute to IBD pathophysiology.[14,15] Two major cell death pathways, the caspase-3 pathway and the recently identified caspase-independent pathway mediated by the activation of poly (ADP-ribose) polymerase-1 (PARP-1), lead to apoptotic cell death following ischemia, inflammatory injury, and ROS-induced injury.[15,16] previous studies have revealed that oxidative stress results in plasma accumulation of AOPPs in IBD,[17,18] the effects of AOPPs on IECs remain unclear It is unknown whether AOPPs affect IEC proliferation and death or intestinal tissue injury.

Methods

Results

Conclusion