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Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis

Wang, Arthur (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Keita, Åsa V. (author)
Östergötlands Läns Landsting,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Kirurgiska kliniken US
Phan, Van (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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McKay, Catherine M. (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Schoultz, Ida, 1979- (author)
Örebro universitet,Institutionen för hälsovetenskap och medicin,Nutrition-Gut-Brain Interactions Research Centre, the Faculty of Medicine, Örebro University, Örebro, Sweden
Lee, Joshua (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Murphy, Michael P. (author)
MRC Mitochondrial Biol Unit, Cambridge, England,MRC-Mitochondrial Biology Unit, Cambridge, United Kingdom
Fernando, Maria (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Ronaghan, Natalie (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Balce, Dale (author)
Joan Snyder Inst Chron Dis, Dept Comparat Biol & Expt Med, Fac Vet Med, Univ Calgary, Calgary AB, Canada,Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
Yates, Robin (author)
Joan Snyder Inst Chron Dis, Dept Comparat Biol & Expt Med, Fac Vet Med, Univ Calgary, Calgary AB, Canada,Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
Dicay, Michael (author)
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Beck, Paul L. (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
MacNaughton, Wallace K. (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
Söderholm, Johan D. (author)
Östergötlands Läns Landsting,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Kirurgiska kliniken US
Mckay, Derek M. (author)
Department of Physiology and Pharmacology, 1877 Health Sciences Center, University of Calgary, Calgary AB, Canada,Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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 (creator_code:org_t)
Elsevier BV, 2014
2014
English.
In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 184:9, s. 2516-2527
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coil with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and transtocation of E. coil across epithelia and control colonic biopsy specimens, which was more striking in Crohn's disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases.

Subject headings

NATURVETENSKAP  -- Biologi -- Immunologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Immunology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Keyword

Patologi
Pathology

Publication and Content Type

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art (subject category)

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