Nitric oxide and carbon monoxide (CO) can be ranked as the first and second gaseous neurotransmitters of interest, while H2S ranks third. It is produced in significant amounts in most tissues, with the highest rates of production in the brain, cardiovascular system, liver, stomach and kidney. H2S exhibits a ‘double-edged’ role in clinical diseases. Thus, it can be detrimental or protective in the central nervous system, exert either pro-inflammatory or anti-inflammatory effects, vaso-relaxation or atherosclerosis. In the gastrointestinal system tract, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), the enzymes responsible for H2S generation, are expressed in the gastric mucosa. Endogenous H2S seems to be a protective factor against mucosal injury, whereas it may contribute pro-inflammatory actions in H. pylori infection. Evidence is accumulating that inhibitors of H2S production, or therapeutic H2S donor compounds, exert significant effects in animal models of inflammation, reperfusion injury and circulatory shock. With respect to NSAIDs, H2S can induce upregulation of anti-inflammatory and cytoprotective genes, including heme oxidase-1 (HO-1), vascular endothelial growth factor, insulin-like growth factor receptor, and several genes associated with the transforming growth factor (TGF)-β receptor signaling pathway. By upregulating HO-1, H2S can trigger the production of CO, another neurotransmitter with well-documented cytoprotective and anti-inflammatory effects exerted by inhibition of NF-κB and inducible nitric oxide synthase (iNOS). Other distinct pharmacological effects of H2S relate to the opening of potassium-opened ATP channels (KAPT channels or KATP) in leukocytes or endothelium, leading to vaso-relaxing and smooth muscle relaxing effects. H2S can also inhibit cellular respiration, at least in part, by acting as an inhibitor of cytochrome c oxidase through an interaction with its copper center. All of these protective roles of H2S have been documented in the following situations; cardioprotection, relieving of inflammation and inflammation-related pain, acceleration of wound healing through angiogenesis, and NSAID-induced gastroenteropathy. Regarding the relationship between NSAID toxicity and leukocyte-endothelial interface, under normal conditions, H2S is synthesized in blood vessels primarily by CSE, which is expressed in endothelial cells and smooth muscle cells. H2S tonically downregulates leukocyte adherence through the activation of KATP on both leukocytes and endothelial cells. However, when synthesis of H2S is suppressed by NSAIDs or β-cyanoalanine, leukocyte rolling and adherence to the vascular endothelium might increase accompanied with a marked increase in endothelial permeability (Fig. 3). Currently, development of H2S as therapeutics in a form of an inhaled gas or parenteral injection is underway as well as modified drugs containing H2S-releasing moieties.42,43
Figure 3. Protective effects of hydrogen sulfide (H2S) against non-steroidal anti-inflammatory drugs (NSAIDs)-induced leukocyte-endothelial interaction. H2S synthesized by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) genes, expressed in endothelial cells or smooth muscle cells tonically downregulates leukocyte adherence through the activation of potassium adenosine triphosphate (ATP) ion channel (KATP) on neutrophil and endothelium. However, when H2S synthesis is inhibited after NSAID administration, leukocyte adherence to vascular endothelium increased and was accompanied with increases in endothelial permeability, resulting in evagination of leukocyte and uropod formation.
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