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.