The Emerging Roles of Hydrogen Sulfide in the Gastrointestinal Tract and Liver

doi:10.1053/j.gastro.2006.02.033

Gastroenterology

Volume 131, Issue 1, July 2006, Pages 259-271

https://doi.org/10.1053/j.gastro.2006.02.033 Get rights and content

Hydrogen sulfide, like nitric oxide, was best known as a toxic pollutant before becoming recognized as a key regulator of several physiologic processes. In recent years, evidence has accumulated to suggest important roles for hydrogen sulfide as a mediator of several aspects of gastrointestinal and liver function. Moreover, alterations in hydrogen sulfide production could contribute to disorders of the gastrointestinal tract and liver. For example, nonsteroidal anti-inflammatory drugs can reduce production of hydrogen sulfide in the stomach, and this has been shown to contribute to the generation of mucosal injury. Hydrogen sulfide has also been shown to play a key role in modulation of visceral hyperalgesia. Inhibitors of hydrogen sulfide synthesis and drugs that can generate safe levels of hydrogen sulfide in vivo have been developed and are permitting interventional studies in experimental models and, in the near future, humans.

Section snippets

Chemistry, Toxicity, and Synthesis

Hydrogen sulfide is a colorless gas with a strong odor that has been widely studied in the context of water and industrial air pollution. Its production is mainly associated with the pulp and paper industry, petroleum refineries, tanneries, and mining. As described in detail later in this article, H₂S can perform many physiologic functions and is produced in many tissues of the body. Toxicity of H₂S is seen at concentrations well above those produced endogenously and is usually associated with

Molecular Biology of CBS and CSE

CBS and CSE are important for the metabolism of sulfur-containing amino acids, as well as for the production of H₂S, ammonium, and pyruvate from L-cysteine. CBS is the predominant H₂S -generating enzyme in the brain and nervous system and is highly expressed in liver and kidney.³ CSE is mainly expressed in the liver and in vascular and nonvascular smooth muscle. A low level of expression of the CSE transcript, protein, and enzymatic activity is also detectable in the small intestine and stomach

Interactions of H₂S and NO

One of the first indications that there may be important interactions between H₂S and NO was the observation that low concentrations of H₂S markedly increased the vasorelaxation induced by an NO donor, sodium nitroprusside.⁷ The mechanism underlying this effect was not clear, but, when it was subsequently shown that H₂S promotes the release of NO from vascular endothelium,⁵² that sodium nitroprusside increased the conversion of L-cysteine to H₂S,⁶ and that this NO donor also increased

Physiologic and Pathophysiologic Actions of H₂S: Neuromodulation

Relatively high concentrations of H₂S (50–160 μmol/L) can be detected in the brain of several mammalian species, including mouse, rat, human, and bovine,54, 55 and recent data have demonstrated that H₂S is also produced in spinal cord tissue.⁵⁶ Awata et al have found expression and activity of CBS and CSE in 6 different rat brain regions, although the activity of CBS was >30-fold greater than that of CSE.⁵⁷ The reduced H₂S production after inhibition of CBS and the fact that CSE inhibitors do

Smooth Muscle

Aside from the possibility of modulating smooth muscle function through its neuromodulatory effects, H₂S can also directly alter smooth muscle tone.⁷ An initial indication of this possibility came from studies demonstrating that low molecular weight S-nitrosothiol intermediates could induce relaxation of coronary smooth muscle and carotid and cerebral arteries.65, 66, 67 The actions of H₂S itself have been studied in vascular tissues,6, 7, 52 and uterine strips from pregnant rats,68, 69 in

Immune and Inflammatory Processes

In recent years, several papers have been published on H₂S in the context of immune and inflammatory reactions. Some papers suggest an anti-inflammatory role of H₂S (Figure 2), whereas others point to a contribution of H₂S to tissue injury and inflammation. H₂S is an extremely potent inhibitor of leukocyte adherence to the vascular endothelium in rat stimulated by intragastric aspirin. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) stimulate leukocyte adherence77, 78, 79

Gastric Mucosal Integrity

Injury to the upper gastrointestinal tract is a common complication of NSAID (including acetylsalicylic) therapy.⁸⁶ Owing largely to the inhibition of COX isoenzymes, NSAIDs reduce the ability of the mucosa to resist injury. Inhibition of generation of COX-1- and COX-2-derived eicosanoids results in altered gastric mucosal blood flow and increased leukocyte-endothelial adhesive interactions in the gastric microcirculation, important events in the process of gastric injury caused by NSAIDs.87, 88

Intestinal Motility and Perception

The possibility that H₂S is an important mediator of gastrointestinal motility has not yet been explored in any detail. There are, however, some data to suggest such a role. Hosoki et al demonstrated that the rat ileum expressed both CBS and CSE mRNA and could synthesize H₂S.⁷ Moreover, ileum precontracted by acetylcholine was relaxed by NaHS in a dose-dependent manner. These data were then confirmed in the ileum of other species. Teague et al demonstrated that NaHS produced dose-related

Hepatic Circulation

Portal hypertension is a multifactorial syndrome characterized by increased hepatic vascular resistance (because of a high hepatic vascular tone) and increased splanchnic blood flow (because of a pronounced splanchnic vasodilatation). A growing body of evidence suggests that the elevated microvascular tone within the cirrhotic liver is a consequence of mechanical factors (disruption of the hepatic vascular bed, scarring, and nodule formation) and vasculogenic processes at the sinusoidal

Conclusions and Future Directions

As was the case for NO 2 decades ago, there is emerging evidence for H₂S in many aspects of gastrointestinal and liver function. H₂S appears to be an important mediator of mucosal and hepatic blood flow and an important contributor to mucosal defense against injury. Deficiencies of H₂S synthesis may contribute to the pathogenesis of several gastrointestinal and liver disorders. Roles for H₂S in inflammation and immunity have been identified but not yet completely defined. Some studies suggest

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Hydrogen sulfide (H₂S) as a critical messenger molecule plays vital roles in regular cell function. However, abnormal levels of H₂S, especially mitochondrial H₂S, are directly correlated with the formation of pathological states including neurodegenerative diseases, cardiovascular disorders, and cancer. Thus, monitoring fluxes of mitochondrial H₂S concentrations both in vitro and in vivo with high selectivity and sensitivity is crucial. In this direction, herein we developed the first ever example of a mitochondria-targeted and H₂S-responsive new generation 1,2-dioxetane-based chemiluminescent probe (). Chemiluminescent probes offer unique advantages compared to conventional fluorophores as they do not require external light irradiation to emit light. exhibited a dramatic turn-on response in its luminescence signal upon reacting with H₂S with high selectivity. It was used to detect H₂S activity in different biological systems ranging from cancerous cells to human serum and tumor-bearing mice. We anticipate that will pave the way for development of new organelle-targeted chemiluminescence agents towards imaging of different analytes in various biological models.
VEGFR<inf>2</inf> in vascular smooth muscle cells mediates H<inf>2</inf>S-induced dilation of the rat cerebral basilar artery
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The aim of present study was to study whether the vascular endothelial growth factor receptor 2 (VEGFR₂) mediates hydrogen sulfide (H₂S)-induced relaxation of the rat cerebral vasculature.
Relaxation of cerebral basilar artery (CBA) and vascular smooth muscle cells (VSMCs) was measured by using a pressure myograph system and image analysis system, respectively. The intracellular calcium concentration ([Ca²⁺]_i) in VSMCs was detected using fluorescence imaging analysis.
We found that H₂S donor NaHS induced significant relaxation of VSMCs from the CBA of wild type rat, but in VEGFR₂ knockdown VSMCs, NaHS-induced relaxation reduced markedly. In addition, NaHS-induced vasodilation of rat CBA also attenuated obviously when the expression of VEGFR₂ was knocked down in vivo. In addition, pretreatment with the VEGFR₂ blocker SU5416 likewise lowered the NaHS-induced relaxation of rat CBA. Nevertheless, the VEGFR₂ agonist, vascular endothelial growth factor 164 (VEGF164), induced a concentration-dependent relaxation of CBA, which is similar to the effect of NaHS. Furthermore, we found that both NaHS and VEGF164 significantly inhibited the U₄₆₆₁₉-induced increase of [Ca²⁺]_i fluorescence intensity in the VSMCs. However, the inhibitory effect of NaHS on the [Ca²⁺]_i fluorescence intensity in VSMCs was markedly inhibited by pretreatment with SU5416 or VEGFR₂ knockdown.
These findings indicated that H₂S-induced CBA dilation and reduction of [Ca²⁺]_i in VSMCs occur by acting on VEGFR₂.
Novel near-infrared spectroscopic probe for visualizing hydrogen sulfide in lysosomes
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Considering the scarcity of hydrogen sulfide (H₂S) probes with subcellular organelle targeting, especially probes with near-infrared (NIR) emission wavelengths fluorophores, our group has been working to overcome this problem and looking forward to providing potential practical tools for exploring the relationship between the physiology and pathology of H₂S at subcellular level. In this paper, a novel colorimetric and NIR fluorescent probe SHCy-H₂S for the specific detection of H₂S in lysosome over other biological thiols was designed and synthesized. The xanthene-benzothiozolium fluorophore was chosen to provide fluorescence emission maxima over 735 nm, and 2,4-dinitrophenyl group was chosen as fluorescence quenching group and specific H₂S response site. Impressively, SHCy-H₂S exhibited high selectivity, fast response and detection limit as low as 0.116 μM for H₂S, marked obvious color changes in naked-eye and fluorescence. Specially, SHCy-H₂S was capable of specifically imaging endogenous lysosomal hydrogen sulfide, providing a potential tool for exploring the function of H₂S at subcellular level.
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Supported by grants from the Canadian Institutes of Health Research (to J.L.W.).

J.L.W. is an Alberta Heritage Foundation for Medical Research Senior Scientist and holds a Canada Research Chair in Inflammation Research.

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Special report and reviewThe Emerging Roles of Hydrogen Sulfide in the Gastrointestinal Tract and Liver

Section snippets

Chemistry, Toxicity, and Synthesis

Molecular Biology of CBS and CSE

Interactions of H2S and NO

Physiologic and Pathophysiologic Actions of H2S: Neuromodulation

Smooth Muscle

Immune and Inflammatory Processes

Gastric Mucosal Integrity

Intestinal Motility and Perception

Hepatic Circulation

Conclusions and Future Directions

Trends Pharmacol Sci

J Chromatogr B Analyt Technol Biomed Life Sci

Biochem Biophys Res Commun

Biomed Pharmacother

Adv Enzyme Regul

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Arch Biochem Biophys

J Biol Chem

J Inorg Biochem

J Biol Chem

Genomics

Arch Biochem Biophys

Biochim Biophys Acta

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

Gastroenterology

J Biol Chem

Am J Obstet Gynecol

J Biol Chem

J Nutr

Biochem Pharmacol

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Trends Pharmacol Sci

Life Sci

Eur J Pharmacol

Gastroenterology

Gastroenterology

Biochem Biophys Res Commun

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

Biochem Biophys Res Commun

Hepatology

Hydrogen sulfide poisoningclarification of some controversial issues

Am J Ind Med

Two’s company, three’s a crowdcan H2S be the third endogenous gaseous transmitter?

FASEB J

Sulfur reduction by human erythrocytes

J Exp Zool

The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener

EMBO J

The possible role of hydrogen sulfide as an endogenous neuromodulator

J Neurosci

Hydrogen sulphide poisoning in a hospital setting

JAMA

A case of acute hydrogen sulphide (H2S) intoxication successfully treated with nitrites

J Formos Med Assoc

Regulation of hepatic glutathione synthesiscurrent concepts and controversies

FASEB J

The production of hydrogen sulfide is regulated by testosterone and S-adenosyl-L-methionine

J Neurochem

Evidence for heme-mediated redox regulation of human cystathionine β-synthase activity

J Biol Chem

Characterization of the heme in human cystathionine β-synthase by X-ray absorption and electron paramagnetic resonance spectroscopies

Biochemistry

Domain architecture of the heme-independent yeast cystathionine β-synthase provides insights into mechanisms of catalysis and regulation

Biochemistry

Special report and review
The Emerging Roles of Hydrogen Sulfide in the Gastrointestinal Tract and Liver

Interactions of H₂S and NO

Physiologic and Pathophysiologic Actions of H₂S: Neuromodulation

Two’s company, three’s a crowdcan H₂S be the third endogenous gaseous transmitter?

The vasorelaxant effect of H₂S as a novel endogenous gaseous K_ATP channel opener

A case of acute hydrogen sulphide (H₂S) intoxication successfully treated with nitrites