Inflammation is a fundamental pathological event, which is described as a protective response to abnormal stimulus. However it is also responsible for a plethora of inflammatory diseases. A major role of hydrogen sulfide is suggested in inflammation, but published results are controversial. In large quantities it is toxic, but it is also produced inside the body during the metabolism of the amino acid cysteine. I propose to provide insight into the molecular mechanisms of how hydrogen sulfide mediates inflammatory events via studying the biochemistry of its interactions with neutrophil white blood cells that are major players in inflammation. We will study its reactions with neutrophil derived oxidants and free radicals. I propose that hydrogen sulfide will either detoxify them or the reactions will generate bioactive products. We will investigate the reactions of hydrogen sulfide and its metabolites with the antimicrobial neutrophil enzyme, myeloperoxidase. We will study the effects of these reactions and products on neutrophil function.
In addition, oxidation and reduction of cysteine residues is an important mechanism of regulating protein function and cell signaling and hydrogen sulfide should readily integrate into these pathways. We will study the redox chemistry of hydrogen sulfide with cysteine derivatives. We will elucidate the kinetics and mechanisms and characterize the products of these reactions. I propose that our study will provide insight into the potential of these reactions in hydrogen sulfide trafficking and regulating in vivo redox homeostasis.
The obtained results should significantly advance our understanding how drugs targeting hydrogen sulfide may be effective. The therapeutic potential of hydrogen sulfide represents a multibillion euro business with many clinical trials in progress. The results of this study will be essential for assessing its toxic versus beneficial health effects as a potential anti-inflammatory drug.
Fields of science
- natural sciencesbiological sciencescell biologycell signaling
- medical and health scienceshealth sciencesinflammatory diseases
- natural scienceschemical scienceselectrochemistryelectrolysis
- natural scienceschemical sciencesorganic chemistryamines
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
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