Gas Biology Research in Clinical Practice

T. Yoshikawa, Y. Naito

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805596657
• Topic: Médecine
• Subtopic: Gastroentérologie et hépatologie

The substantial biological importance of gaseous mediators in various physiological-pathological conditions has been realized only recently, but to date, the detailed mechanisms involved remain elusive. The publication at hand contains 16 overviews written by a panel of experts who summarize the current knowledge and provide fundamental insights into the roles of gaseous molecules in signal transduction in biological systems. The first part provides a comprehensive overview on gaseous mediators in health and disease. In the second part, the medical application of various molecules such as nitric oxide, carbon monoxide, hydrogen sulfide, hydrogen, acetone and phytoncide are discussed. Furthermore, articles on skin gas biology and Carbon-13 (13C), especially clinical applications of 13C-labeled substrate are included. This book provides valuable information not only for basic researchers in physiology and biochemistry, but also for gastroenterologists and clinicians who wish to learn more about the role of gaseous mediators.

Gas and Medical Application: III. H₂S

Yoshikawa T, Naito Y (eds): Gas Biology Research in Clinical Practice.
Basel, Karger, 2011, pp 65–72

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Hydrogen Sulfide in the Gastrointestinal Tract: Friend or Foe?

Chan Young Ock^a · So Jung Han^b · Ki-Seok Choi^a · Eun-Hee Kim^a · Ju Hyun Kim^b · Ki-Baik Hahm^a,b

^aLaboratory of Translational Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, and ^bDepartment of Gastroenterology, Gachon University Graduate School of Medicine, Incheon, Korea

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Abstract

Hydrogen sulfide (H₂S) has been engaged in the reversible state of hypothermia, suspended animation-like states, and halitosis in vertebrates. In the gastrointestinal (GI) tract, H₂S has been put on the chopping board since a rather conflicting fact exists that inhibition of H₂S production causing obstacles in recovery from various animal models of inflammation, reperfusion injury, and compromised circulation or the possibility of therapeutic exploitation of H₂S or its donor compounds based on their anti-inflammatory and circulatory preservation. As a third gasotransmitter, together with nitric oxide and carbon monoxide, there are complex interactions between these mediators in their contribution to regulating cell function, vascular responses, and inflammatory reactions. In spite of these double-edged roles, many concerns have focused on H₂S as a potential therapeutic or a newer pathophysiological player. In this chapter, we describe the benevolence or notoriety of H₂S in the GI tract.

Copyright © 2011 S. Karger AG, Basel

Small-molecular-weight gases including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) constitute a unique class of biomaterials that are indispensable for maintaining the homeostasis of biological systems. They serve as a substance that readily conveys the signal from one site to another in an autocrine, paracrine or juxtacrine fashion since the gases are highly membrane-permeable. These gases exert their biological actions through interactions with proteins in multiple ways distinct from other signaling molecules. Interestingly, not only can different gases that share a similar chemical structure exert comparable biological actions but they often compete with and are antagonists to each other, showing that a single, small molecule such as a gas could affect various signaling pathways when exposed to an individual cell. Before there was enough understanding of the biologic roles of gases, we just thought of these gases as being either simple byproducts or waste material that needed to be discarded. However, with increasing evidence showing that they have more biologic roles than we realized - gases can easily penetrate the cell barrier and move faster than other signal molecules -, their impact on the whole body system seems to be far greater than that of conventional signaling molecules such as hormones and neurotransmitters [1, 2].

The first biogas that was seen to have a potent impact on the human body was NO. It was found by Drs. Furchgott, Murad, and Ignarro who were honored for their discovery by being awarded the Nobel Prize for medicine in 1998. Even though the studies of endothelium-derived relaxing factor (EDRF) and nitrovasodilators were discovered separately, two tales finally merged by finding the exact biological similarity of EDRF and NO. NO is synthesized from oxygen and L-arginine by NO synthase, and has major physiologic functions as a vasodilator, platelet aggregator, and neurotransmitter. It is known that NO interacts with various biomolecules that contain heme group-like guanylyl cyclase or cytochrome P450, and modulates the thiol status by interrupting the cysteine residues of proteins. As the second endogenous gas of interest, CO was discovered as an endogenously produced mediator and neurotransmitter. CO is synthesized during the metabolism of heme to biliverdin by heme oxidase-1 (HO-1). Generally known as a toxic gas produced by burning coal, CO asphyxia could cause serious damage since the affinity to hemoglobin is much higher with CO than with oxygen. However, increasing evidence has shown that CO can scavenge reactive oxygen species, regulate vascular muscle tone, or transmit neural signals to the brain, meaning that CO is a crucial mediator for maintaining physiological homeostasis [3, 4]. H₂S, the third gas of interest and importance, was also first known as a ‘toxic gas’ because for decades it was only known as a toxic environmental pollutant and principal offender of halitosis based on its strong odor of rotten eggs [5]. Even though, at the end of 1980s, endogenous hydrogen sulfide was found in the brain, it was suggested to be an artifact until Drs. Abe and Kimura described the enzymatic mechanism of H₂S production in the brain, its biological effects at physiological concentrations, and its specific cellular targets. H₂S is synthesized endogenously in various mammalian tissues by two pyridoxal-5’-phosphate-dependent enzymes responsible for metabolizing L-cysteine: cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) [6]. The substrate of CBS and CSE, L-cysteine, is a sulfur-containing amino acid and can be derived from gastrointestinal (GI) sources or liberated from endogenous proteins. However, beyond this notoriety, increasing evidence has shown that H₂S could exert its beneficial physiological roles including the regulation of vasodilatation, attenuation of inflammation and modulation of gut signaling molecules, after which it became a key new therapeutic target, for instance, in the development of GI-safe NSAIDs, endotoxemia-induced gut injury, and GI motility disorders in the GI tract. In this chapter, we will focus on the role of H₂S in the GI system, providing both of its aspects: integrating the initiation and progression of GI diseases in a friendly or hostile manner.

Benevolent Role of H₂S Gas in the Gastrointestinal Tract

Administration of H₂S produced a ‘suspended animation-like’ metabolic status with hypothermia and reduced oxygen demand in pigs and mice, thus protecting from lethal hypoxia. This hypometabolic state, which resembles hibernation, induced by H₂S may contribute to tolerance against oxidative stress [7]. In addition, the antioxidant effects of H₂S can be explained by its effects on cytochrome c oxidase and mitochondrial functions, while its effects on gene expression may be related to actions on the the NF-κB and extracellular signal-regulated kinase pathways [8]. These antioxidant effects of H₂S are reported to be dependent on its concentration and the cellular status of the host. At micromolar concentrations, the cytoprotective effects of H₂S are usually produced by Na₂S or NaHS which can scavenge groups of reactive species including oxyradicals, peroxynitrite, hypochlorous acid and homocysteine [9]. Not does on...