Hydrogen sulphide induces HIF-1α and Nrf2 in THP-1 macrophages

Lohninger, Lilian; Tomášová, Lenka; Praschberger, Monika; Hintersteininger, Michael; Erker, Thomas; Gmeiner, Bernhard; Laggner, Hilde

doi:10.1016/j.biochi.2015.03.009

Cited by 42 publications

(40 citation statements)

References 50 publications

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“…First of all, did the NaHS infusion alter the progression of infection and was organ colonization affected by NaHS in the current study? Importantly, H 2 S can affect bacterial virulence and the sensitivity of bacteria to antibiotic treatment, at least in vitro (24,25) and H 2 S can also affect host immune function (26–28). It is, therefore, also conceivable that H 2 S (produced endogenously during sepsis, and/or when administered in the form of NaHS) may also have affected bacterial replication, organ invasion and/or the sensitivity of the bacteria to elimination by the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…fact that the beneficial effect of NaHS was rather rapid (it was administered at 24 hours, and changes in various parameters were already affected 6h later) - tends to speak against this possibility, the issue of the role of of H 2 S in bacterial virulence/growth during sepsis remain to be addressed in future studies. Moreover, H 2 S is also known to impact macrophage function (26); future studies are needed to address whether the effect of H 2 S on macrophage function may have contributed to the reduced inflammatory response and/or to the potentially altered course of bacterial infection. n responsible for the improvements in outcome.…”

Section: Discussionmentioning

confidence: 99%

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Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Ahmad

Druzhyna

Szabó³

2016

Shock

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Cecal ligation and puncture (CLP) induced sepsis is a serious medical condition, caused by a severe systemic infection resulting in a systemic inflammatory response. Recent studies have suggested the therapeutic potential of donors of hydrogen sulfide (H2S), a novel endogenous gasotransmitter and biological mediator in various diseases. The aim of the present study was to assess the effect of H2S supplementation in sepsis, with special reference to its effect on the modulation of regional blood flow. We infused sodium hydrosulfide (NaHS), a compound that produces H2S in aqueous solution (1, 3 or 10 mg/kg/h, for 1 hour at each dose level) in control rats or rats 24 hours after CLP, and measured blood flow using fluorescent microspheres. In normal control animals, NaHS induced a characteristic redistribution of blood flow, and reduced cardiac, hepatic and renal blood flow in a dose-dependent fashion. In contrast, in rats subjected to CLP, cardiac, hepatic and renal blood flow was significantly reduced; infusion of NaHS (1 mg/kg/h and 3 mg/kg/h) significantly increased organ blood flow. In other words, the effect of H2S on regional blood flow is dependent on the status of the animals (i.e. a decrease in blood flow in normal controls, but an increase in blood flow in CLP). We have also evaluated the effect of delayed treatment with NaHS on organ dysfunction and the inflammatory response by treating the animals with NaHS (3 mg/kg) intraperitoneally (i.p) at 24 h after the start of the CLP procedure; plasma levels of various cytokines and tissue indicators of inflammatory cell infiltration and oxidative stress were measured 6 hours later. After 24 h of CLP, glomerular function was significantly impaired, as evidenced by markedly increased (over 4-fold over baseline) blood urea nitrogen and creatinine levels; this increase was also significantly reduced by treatment with NaHS. NaHS also attenuated the CLP-induced increases in malondialdehyde levels (an index of oxidative stress) in heart as well as in liver and myeloperoxidase levels (an index of neutrophil infiltration) in heart and lung. Plasma levels of IL-1β, IL-5, IL-6, TNF-α and HMGB1 were attenuated by NaHS. Treatment of NaHS at 3 mg/kg i.p, (but not 1 mg/kg or 6 mg/kg), starting 24 hours post-CLP, with dosing repeated every 6 h, improved the survival rate in CLP animals. In summary, treatment with 3 mg/kg H2S - when started in a delayed manner, when CLP-induced organ injury, inflammation and blood flow redistribution have already ensued - improves blood flow to several organs, protects against multiple organ failure, and reduces the plasma levels of multiple pro-inflammatory mediators. These findings support the view that H2S donation may have therapeutic potential in sepsis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Ahmad

Druzhyna

Szabó³

2016

Shock

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“…At high concentrations, nitric oxide inhibits HIF hydroxylases, which leads to increased HIF activity, whereas lower concentrations of this gas inhibit mitochondrial oxygen consumption; this inhibition decreases HIF activity as intracellular oxygen is redistributed from the mitochondria to the oxygen-sensing HIF hydroxylases, such as PHDs and FIH 26,75 We have recently reported that elevated concentrations of carbon dioxide (CO 2 ), which occur during increased metabolism and dysregulated respiration, can suppress HIF activity by targeting HIF for lysosomal degradation 29 . Recent work has also identified that hydrogen sulfide (H 2 S) can also regulate HIF activity 76–78 . Importantly, all of these physiological gases have been shown to be altered in pathological states, such as chronically inflamed or infected tissues or growing tumours.…”

Section: Niche Features That Shape the Hif Responsementioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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“…In CBS −/− mice, another factor that could contribute to reduced expression of Fpn1 is NRF2. NRF2, a transcription factor that regulates antioxidant genes, has been known to affect Fpn1 expression and cell‐iron release and can be activated by the H 2 S donors GYY4137 and sodium hydrosulfide . Impaired NRF2 expression can reduce Fpn1 transcription and then diminish iron egress in mouse and human cells .…”

Section: Discussionmentioning

confidence: 99%

Cystathionine β‐synthase is required for body iron homeostasis

Zhou

Zhang

et al. 2017

Hepatology

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Cystathionine b-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS 2/2 ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBSoverexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Conclusion: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosislike phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (HEPATOLOGY 2018;67:21-35) C ystathionine b-synthase (CBS) was first isolated in the liver by Braunstein et al.(1) in 1969. The location of the human CBS gene is on chromosome 21 (43.35-43.37 Mb).(2) CBS is a key enzyme for hydrogen sulfide (H 2 S) production from L-cysteine, in addition to cystathionine gammalyase and 3-mercaptopyruvate sulfurtransferase. (2,3) H 2 S has been implicated as the third endogenous gas transmitter, after nitric oxide and carbon monoxide, functioning in the brain as well as peripheral organs.(2,3) CBS deficiency, induced by mutation in the CBS gene, is a rare autosomal recessive disorder characterized by highly elevated levels of total plasma homocysteine.(4) Patients not treated in infancy have multisystem disorders including arterial occlusions, venous thromboembolisms, osteoporosis, intellectual disabilities, psychiatric disorders, and dislocated lenses.(4,5) Homozygous knockout mice (CBS 2/2 ) rarely survive past 4 weeks of age, (2) implying that CBS is essential for survival and development in mice. It has been demonstrated that H 2 S has a significant effect on the regulation of proinflammatory cytokines including interleukin-6 (IL-6) (6) and signal transducer and activator of transcription 3 (STAT3) activity. (7)(8)(9)(10) Abbreviations: Ad, adenovirus; BMDM, bone marrow-derived macrophage; CBS, cystathionine b-synthase; 9 (11) -dien-28-oyl] imidazole; DMT1, d...

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Hydrogen sulphide induces HIF-1α and Nrf2 in THP-1 macrophages

Cited by 42 publications

References 50 publications

Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

Regulation of immunity and inflammation by hypoxia in immunological niches

Cystathionine β‐synthase is required for body iron homeostasis

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