Abstract
Reactive oxygen species (ROS) have been the focus of redox research in the realm of oxidative neonatal respiratory diseases such as bronchopulmonary dysplasia (BPD). Over the years, nitric oxide (NO) and carbon monoxide (CO) have been identified as important gaseous signaling molecules involved in modulating the redox homeostasis in the developing lung. While animal data targeting aspects of these redox pathways have been promising in treating and/or preventing experimental models of neonatal lung disease, none are particularly effective in human neonatal clinical trials. In recent years, hydrogen sulfide (H2S) has emerged as a novel gasotransmitter involved in a magnitude of cellular signaling pathways and functions. The importance of H2S signaling may lie in the fact that early life-forms evolved in a nearly anoxic, sulfur-rich environment and were dependent on H2S for energy. Recent studies have demonstrated an important role of H2S and its synthesizing enzymes in lung development, which normally takes place in a relatively hypoxic intrauterine environment. In this review, we look at clues from evolution and explore the important role that the H2S signaling pathway may play in oxidative neonatal respiratory diseases and discuss future opportunities to explore this phenomenon in the context of neonatal chronic lung disease.
Highlights
In the 3-mercaptopyruvate sulfurtransferase (3-MST)-related pathway of H2 S production, cysteine is initially converted through the enzyme cysteine aminotransferase to 3-mercaptopyruvate (3-MP), which acts as a substrate for 3-MST to produce an enzyme-bound persulfide, which in turn can give rise to H2 S [46]
H2 S metabolism is tightly controlled through the mitochondrial sulfide oxidation pathway, which acts as a bridge to the electron transport chain (ETC) at the level of complex
(nuclear factor kappa-light-chain-enhancer of activated B cells), which is an essential transcription factor for antiapoptotic activity, is activated by H2 S through persulfidation of its p65 subunit at Cys38 [78]. Another transcription factor known as SP1, which is a regulator of endothelial function, is persulfidated at multiple cysteine residues, which in turn modulates vascular endothelial growth factor (VEGF) and neuropilin-1 expression [79]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Several antioxidant mechanisms are active in the lungs of premature babies to counteract the effects of oxidants, which include the glutathione (GSH) and thioredoxin (Trx) systems, superoxide dismutase (SOD), and catalase, among others. H2 S and its synthesizing enzymes have been shown to play an important role in lung and airway development [8,9,10], raising the question: ‘Is H2 S the missing link in the lung redox homeostasis?’ To answer this intriguing question, we will have to look at evolutionary clues and understand the context in which these various redox systems developed and evolved under different oxidative environments.
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