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Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia‐inducible factor‐1α
Author(s) -
Flannigan Kyle L.,
Agbor Terence A.,
Motta JeanPaul,
Ferraz José G. P.,
Wang Rui,
Buret Andre G.,
Wallace John L.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-266015
Subject(s) - colitis , hypoxia (environmental) , chemistry , inflammation , inflammatory bowel disease , pharmacology , immunology , medicine , oxygen , disease , organic chemistry
During a course of colitis, production of the gaseous mediator hydrogen sulfide (H 2 S) is markedly up‐regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H 2 S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H 2 S 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 H 2 S‐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 H 2 S production led to decreased HIF‐1α stabilization and exacerbation of colitis. Furthermore, application of an H 2 S‐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 H 2 S production and may represent a negative feedback mechanism to prevent prolonged HIF‐1α stabilization. Our findings demonstrate an important link between H 2 S and HIF‐1α in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value of H 2 S donors.—Flannigan, K. L., Agbor, T. A., Motta, J. ‐P., Ferraz, J. G. P., Wang, R, Buret, A. G., Wallace, J. L. Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia‐inducible factor‐1α. FASEB J. 29, 1591‐1602 (2015). www.fasebj.org