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11.	Wang, Arthur, et al. (author) Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis 2014 In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 184:9, s. 2516-2527 Journal article (peer-reviewed)abstract 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.

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Result 11-11 of 11

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Type of publication: journal article (9); doctoral thesis (1); research review (1)

Type of content: peer-reviewed (10); other academic/artistic (1)

Author/Editor: Söderholm, Johan D (8); Keita, Åsa (6); Keita, Åsa V. (4); Campbell, Barry J (3); Roberts, Carol L. (3); Rhodes, Jonathan M. (3); show more...; Ericson, Ann-Charlot ... (2); Parsons, Bryony N. (2); O'Kennedy, Niamh (2); Mckay, Derek M. (1); Schoultz, Ida, 1979- (1); Santos, Javier (1); Martinez, Cristina (1); O’Brien, David (1); Gustafsson, Jenny K, ... (1); Ermund, Anna (1); Hansson, Gunnar C., ... (1); Magnusson, Karl-Eric ... (1); Vanuytsel, Tim (1); Tack, Jan (1); Vicario, Maria (1); Farre, Ricard (1); Vanheel, Hanne (1); Murphy, Michael P. (1); McKay, D. M. (1); Carlsson, Anders, 19 ... (1); Söderholm, Johan D., ... (1); Keita, Åsa, Dr. (1); Weström, Björn, Prof ... (1); Prorok-Hamon, Maelle (1); Van Oudenhove, Lukas (1); Salisbury, Anne-Mari ... (1); Dabrosin Söderholm, ... (1); Wang, Arthur (1); Wigley, Paul (1); Carlsson, A H. (1); Cigehn, M (1); Williams, Jonathan M ... (1); Phan, Van (1); Knight, Paul (1); Duncan, Sylvia H. (1); Dicay, Michael (1); MacNaughton, Wallace ... (1); Fry, Stephen C. (1); Simpson, Hannah L. (1); Humphrey, Suzie (1); Watson, Alastair J. ... (1); Winstanley, Craig (1); O´Kennedy, Niamh (1); McKay, Catherine M (1); show less...

University: Linköping University (11); University of Gothenburg (1); Örebro University (1)

Language: English (11)

Research subject (UKÄ/SCB): Medical and Health Sciences (2); Natural sciences (1)

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