Hydrogen sulfide (H2S) has emerged as an important mediator of host function. In the gastrointestinal tract H2S is enzymatically produced and plays a vital role in cytoprotection, inflammation, and tissue repair. During a bout of colitis, the ability of the colon to produce H2S is markedly increased and drives the resolution of colitis. However, little is known about how the production of H2S is regulated in the colon and how dysregulated production can affect the course of colitis in vivo. Additionally, the mechanisms through which H2S can promote the resolution of colitis remain to be fully investigated.
In Chapter 3 of this dissertation, the regulation of H2S production in the colon was explored by examining the contributions of three enzymatic pathways to colonic H2S synthesis. The largest source of the H2S synthesis was from a pathway previously unrecognized in the GI tract involving the enzyme 3-mercaptopyruvate sulfurtransferase (3MST). Additionally we found that the upregulation of H2S production during colitis occurred specifically at sites of mucosal ulceration. At the same time H2S inactivation via the enzyme sulfide quinone reductase (SQR) was significantly reduced at these sites. We propose that the site-specific alterations in H2S production and inactivation during colitis promote the resolution of inflammation and injury.
Chapter 4 examined whether the ability of hyperhomocysteinemia (Hhcy) to exacerbate colonic inflammation occurred through impaired H2S synthesis. Hyperhomocysteinemia is often reported in patients with inflammatory bowel disease and is a consequence of decreased vitamin B intake. In all three models tested, diet-induced Hhcy significantly exacerbated colitis. Being dependent on vitamin B6 as a co-factor, the increased H2S production normally observed during colitis was abolished during Hhcy. Administration of an H2S donor to Hhcy rats significantly decreased the severity of colitis. These results also uncovered a novel role for IL-10 in promoting H2S production and homocysteine metabolism, which may have therapeutic value in conditions characterized by Hhcy.
Finally, in Chapter 5 we looked for a mechanism through which H2S can promote resolution of colitis. Using CSE-deficient mice we found that H2S production was required to maintain HIF-1α signaling in the colon. Additionally, proper HIF-1α signaling was required for H2S-donating molecules to promote the resolution of colitis. These results suggest that HIF-1α signaling is a critical event through which H2S promotes resolution of colitis. Collectively, these chapters further highlight the importance of H2S production in colon during inflammation and injury and offer insight into new therapeutic targets mediated through H2S. / Dissertation / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/16460 |
| Date | 11 1900 |
| Creators | Flannigan, Kyle L |
| Contributors | Wallace, John L, Health Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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