HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsKyle L Flannigan, Terence A Agbor, Jean-Paul Motta, José G P Ferraz, Rui Wang, Andre G Buret, John L Wallace
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 4 Pg. 1591-602 (Apr 2015) ISSN: 1530-6860 [Electronic] United States
PMID25550470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© FASEB.
Chemical References
  • 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
  • Allyl Compounds
  • Benzenesulfonates
  • Disulfides
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mustard Compounds
  • Phenylpropionates
  • dinitrobenzenesulfonic acid
  • diallyl disulfide
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide
Topics
  • Allyl Compounds (pharmacology)
  • Animals
  • Benzenesulfonates (toxicity)
  • Colitis (drug therapy, metabolism, pathology)
  • Cystathionine gamma-Lyase (antagonists & inhibitors, metabolism)
  • Disease Models, Animal
  • Disulfides (pharmacology)
  • Gene Expression
  • HT29 Cells
  • Humans
  • Hydrogen Sulfide (metabolism)
  • Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mustard Compounds (pharmacology)
  • Phenylpropionates (pharmacology)
  • Protein Stability
  • Rats
  • Rats, Wistar
  • Wound Healing (drug effects, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: