title: 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.
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.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: F
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Huizhou Medical Institute, Huizhou, China.
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Orthopedic and Spinal Surgery, Southern Medical University, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Xue
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: P
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Orthopedic and Spinal Surgery, Southern Medical University, Guangzhou, China.
authors.forename: J H
authors.initials: JH
authors.lastname: Zeng
authors.affiliation: 1] Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Huiqiao Building, Southern Medical University, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Bai
mesh_terms: D000293:Adolescent; D000328:Adult; D062107:Advanced Oxidation Protein Products / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology; D005260:Female; D006801:Humans; D007422:Intestines / Q000166:cytology* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D062107:Advanced Oxidation Protein Products; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases