Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α

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)-1 alpha. 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 gamma-lyase (CSE), and HIF-1 alpha 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-1 alpha stabilization and exacerbation of colitis. Furthermore, application of an H2S-releasing molecule, diallyl disulfide (DADS), stabilized colonic HIF-1 alpha 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-1 alpha in vivo (PX-478). DADS was also able to maintain HIF-1 alpha expression at a later point incolitis, when HIF-1 alpha levels would have normally returned to control levels, and to enhance resolution. Finally, we found that HIF-1 alpha stabilization inhibited colonic H2S production and may represent a negative feedback mechanism to prevent prolonged HIF-1 alpha stabilization. Our findings demonstrate an important link between H2S and HIF-1 alpha in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value ofH(2)S donors.