Hydrogen Sulfide in Inflammation: A Novel Mediator and Therapeutic Target

Bhatia, Madhav; Gaddam, Ravinder Reddy

doi:10.1089/ars.2020.8211

Cited by 50 publications

(38 citation statements)

References 63 publications

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“…Our findings highlight the importance of central TRPA1-mediated H 2 S signaling in the thermoregulation system. In severe forms of systemic inflammation (e.g., septic shock), which is often associated with hypothermia [ 83 ] and by enhanced production of H 2 S [ 40 , 84 ], the interaction between TRPA1 and H 2 S can play a crucial role in the development of the response and, as perspective, may serve as a therapeutic target. Furthermore, the H 2 S-induced activation of central TRPA1 channels may pave the road to the development of controlled induction of hypothermia, but future research is needed to reveal the true thermopharmacological potential of the central TRPA1-H 2 S interaction in health and disease.…”

Section: Discussionmentioning

confidence: 99%

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

et al. 2021

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Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1−/−) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1−/− mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

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Section: Discussionmentioning

confidence: 99%

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

et al. 2021

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“…Besides ROS, other endogenous small, reactive signaling molecules include reactive nitrogen species (RNS), such as nitric oxide, as well as hydrogen sulfide and carbon monoxide. Several reviews discuss their roles in macrophage function (7)(8)(9), so they will not be considered in the present review.…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species in Macrophages: Sources and Targets

et al. 2021

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Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the “all or none” pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources.

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“…Accumulating evidence suggests that H 2 S plays an important role in inflammation [13,73,74]. To evaluate the anti-inflammatory properties of P* in comparison to NaHS, we used IL-6 production as a read-out because this cytokine is abundantly expressed in ATDC5 cells as well as in primary chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling

et al. 2021

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Hydrogen sulfide (H2S) is an important mediator of inflammatory processes. However, controversial findings also exist, and its underlying molecular mechanisms are largely unknown. Recently, the byproducts of H2S, per-/polysulfides, emerged as biological mediators themselves, highlighting the complex chemistry of H2S. In this study, we characterized the biological effects of P*, a slow-releasing H2S and persulfide donor. To differentiate between H2S and polysulfide-derived effects, we decomposed P* into polysulfides. P* was further compared to the commonly used fast-releasing H2S donor sodium hydrogen sulfide (NaHS). The effects on oxidative stress and interleukin-6 (IL-6) expression were assessed in ATDC5 cells using superoxide measurement, qPCR, ELISA, and Western blotting. The findings on IL-6 expression were corroborated in primary chondrocytes from osteoarthritis patients. In ATDC5 cells, P* not only induced the expression of the antioxidant enzyme heme oxygenase-1 via per-/polysulfides, but also induced activation of Akt and p38 MAPK. NaHS and P* significantly impaired menadione-induced superoxide production. P* reduced IL-6 levels in both ATDC5 cells and primary chondrocytes dependent on H2S release. Taken together, P* provides a valuable research tool for the investigation of H2S and per-/polysulfide signaling. These data demonstrate the importance of not only H2S, but also per-/polysulfides as bioactive signaling molecules with potent anti-inflammatory and, in particular, antioxidant properties.

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Hydrogen Sulfide in Inflammation: A Novel Mediator and Therapeutic Target

Cited by 50 publications

References 63 publications

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

Reactive Oxygen Species in Macrophages: Sources and Targets

Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling

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