title: Intrarectal administration of oxygenated perfluorodecalin promotes healing of murine colitis by targeting inflammatory hypoxia.
abstract: Intestinal inflammation is associated with enhanced mucosal hypoxia, which contributes to the ongoing inflammatory process and hampers appropriate mucosal healing. We questioned whether local treatment with an oxygen (O(2))-carrying and -releasing molecule (oxygenated perfluorodecalin, O(2)-PFD) could positively influence the course of experimental colitis. The impact of intrarectal (IR) treatment with O(2)-PFD was tested using the murine dextran sodium sulfate (DSS)-induced model of distal colitis, both in preventive and therapeutic settings. Colonic mucosal hypoxia was visualized by pimonidazole staining. Colonic permeability was evaluated with FITC-dextran. In the preventive study, mice treated with O(2)-PFD were protected against DSS colitis compared with saline-treated mice, as demonstrated by reduced shortening of colon length, reduced colonic tumor necrosis factor-alpha levels and a lower histological inflammation score (P<0.05 for all parameters). In the therapeutic study, administration of O(2)-PFD resulted in accelerated recovery of colitis compared with saline-treated littermates, and this was reflected by a better weight evolution, lower myeloperoxidase activity and a lower histological inflammation score (P<0.05 for all parameters). It was found that O(2)-PFD established its therapeutic effects through (1) intrinsic anti-inflammatory effects of the PFD molecule and (2) O(2)-induced preservation and healing of the intestinal epithelial surface. Further in vitro and in vivo studies showed that the barrier-protective activity of O(2)-PFD was obtained through prevention of colonocyte apoptosis and stimulation of colonocyte proliferation during inflammatory hypoxia. These data show that IR treatment with O(2)-PFD promotes colitis healing by the combined actions of direct anti-inflammatory effects and O(2)-induced restitution of the epithelial barrier. As such, O(2)-PFD enemas could be an attractive treatment option for patients with distal inflammatory bowel disease.
authors.affiliation: Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium. Pieter.Hindryckx@UGent.be
authors.forename: Pieter
authors.initials: P
authors.lastname: Hindryckx
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.forename: Debby
authors.initials: D
authors.lastname: Laukens
authors.forename: Koen
authors.initials: K
authors.lastname: Venken
authors.forename: Harald
authors.initials: H
authors.lastname: Peeters
authors.forename: Martine
authors.initials: M
authors.lastname: De Vos
mesh_terms: D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D004333:Drug Administration Routes; D005466:Fluorocarbons / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D000860:Hypoxia / Q000188:drug therapy* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010100:Oxygen / Q000737:chemistry*; D012007:Rectum
chemical_list: D005466:Fluorocarbons; C008805:perfluorodecalin; D010100:Oxygen