title: Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α.
abstract: During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up-regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S in experimental colitis are mediated via stabilization of hypoxia-inducible factor (HIF)-1α. The hapten dinitrobenzene sulfonic acid was used to induce colitis in rats and mice. This resulted in an elevated expression of the H2S-producing enzyme, cystathionine γ-lyase (CSE), and HIF-1α at sites of mucosal ulceration, and the expression of these 2 enzymes followed a similar pattern throughout the course of colitis. This represented a functionally important relationship because the loss of CSE-derived H2S production led to decreased HIF-1α stabilization and exacerbation of colitis. Furthermore, application of an H2S-releasing molecule, diallyl disulfide (DADS), stabilized colonic HIF-1α expression, up-regulated hypoxia-responsive genes, and reduced the severity of disease during peak inflammation. Importantly, the ability of DADS to promote the resolution of colitis was abolished when coadministered with an inhibitor of HIF-1α in vivo (PX-478). DADS was also able to maintain HIF-1α expression at a later point in colitis, when HIF-1α levels would have normally returned to control levels, and to enhance resolution. Finally, we found that HIF-1α stabilization inhibited colonic H2S production and may represent a negative feedback mechanism to prevent prolonged HIF-1α stabilization. Our findings demonstrate an important link between H2S and HIF-1α in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value of H2S donors.
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Flannigan
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Agbor
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Motta
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: José G P
authors.initials: JG
authors.lastname: Ferraz
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
authors.affiliation: *Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada altapharm@hotmail.com.
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004220:Disulfides / Q000494:pharmacology; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009150:Mustard Compounds / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D055550:Protein Stability; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D000498:Allyl Compounds; D001557:Benzenesulfonates; D004220:Disulfides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; C007488:dinitrobenzenesulfonic acid; C028009:diallyl disulfide; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: gasotransmitter; healing; inflammation; inflammatory bowel disease; ulcer