Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic micorcirculatory dysfunction during endotoxemia

Hydrogen sulfide (H2S) affects vascular resistance; however, its effect on the hepatic microcirculation has not been investigated. Hepatic sinusoidal perfusion is dysregulated during sepsis, contributing to liver injury. Therefore, the present study determined the effect of H2S on the hepatic microcirculation and the contribution of endogenous H2S to hepatic microcirculatory dysfunction in an endotoxin model of sepsis. Portal infusion of H2S increased portal pressure in vivo (6.8 ± 0.2 mmHg before H2S vs. 8.6 ± 0.8 mmHg peak during H2S infusion, P < 0.05). Using intravital microscopy, we observed decreased sinusoidal diameter (6.2 ± 0.27 μm before H2S vs. 5.7 ± 0.3 μm after H2S, P < 0.05) and increased sinusoidal heterogeneity during H2S infusion ( P < 0.05) and net constriction. Since hepatic H2S levels are elevated during sepsis, we used the cystathionine γ lyase inhibitor dl-propargylglycine (PAG) to determine the contribution of H2S to the hypersensitization of the sinusoid to the vasoconstrictor effect of endothelin-1 (ET-1). PAG treatment significantly attenuated the sinusoidal sensitization to ET-1 in endotoxin-treated animals. ET-1 infusion increased portal pressure to 175% of baseline in endotoxemic animals, which was reduced to 143% following PAG treatment ( P < 0.05). PAG abrogated the increase in sinusoidal constriction after ET-1 infusion in LPS-treated rats (30.9% reduction in LPS rats vs. 11.6% in PAG/LPS rats, P < 0.05). Moreover, PAG treatment significantly attenuated the increase in NADH fluorescence following ET-1 exposure during endotoxemia (61 grayscale units LPS vs. 21 units in PAG/LPS, P < 0.05), suggesting an improvement in hepatic oxygen availability. This study is the first to demonstrate a vasoconstrictor action of H2S on the hepatic sinusoid and provides a possible mechanism for the protective effect of PAG treatment during sepsis.

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Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation

Clinical Science ◽

10.1042/cs20190514 ◽

2019 ◽

Vol 133 (20) ◽

pp. 2045-2059 ◽

Cited By ~ 4

Author(s):

Da Zhang ◽

Xiuli Wang ◽

Siyao Chen ◽

Selena Chen ◽

Wen Yu ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Endothelial Cell ◽

Pulmonary Artery ◽

Cell Model ◽

Site Directed Mutagenesis ◽

Critical Event ◽

Hypertensive Rats ◽

Pulmonary Artery Endothelial Cell

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

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In vivo imaging of liver injury and regeneration by functional two-photon microscopy

Zeitschrift für Gastroenterologie ◽

10.1055/s-0036-1597342 ◽

2016 ◽

Vol 54 (12) ◽

pp. 1343-1404

Author(s):

A Ghallab ◽

R Reif ◽

R Hassan ◽

AS Seddek ◽

JG Hengstler

Keyword(s):

Liver Injury ◽

In Vivo Imaging ◽

Two Photon Microscopy ◽

Two Photon

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Faculty Opinions recommendation of In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718006875.793500030 ◽

2014 ◽

Author(s):

Isao Sakaida ◽

Taro Takami

Keyword(s):

Liver Injury ◽

Therapeutic Effects

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Faculty Opinions recommendation of Making and working with hydrogen sulfide: The chemistry and generation of hydrogen sulfide in vitro and its measurement in vivo: a review.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718030784.793480292 ◽

2013 ◽

Author(s):

Robert Poole

Keyword(s):

Hydrogen Sulfide

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ADT-OH, a Hydrogen Sulfide-Releasing Donor, Induces Apoptosis of Melanoma Cells and Inhibits Melanoma Development In Vivo

SSRN Electronic Journal ◽

10.2139/ssrn.3324732 ◽

2019 ◽

Author(s):

Fangfang Cai ◽

Nini Cao ◽

Xiangyu Zhang ◽

Jia Liu ◽

Huangru Xu ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Melanoma Cells

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In vivo protective effect against ethanol metabolism and liver injury of oyster (Crassostrea Gigas) extracts obtained via subcritical water processing

Food Science and Biotechnology ◽

10.1007/s10068-021-00941-9 ◽

2021 ◽

Author(s):

Hee-Jeong Lee ◽

Periaswamy Sivagnanam Saravana ◽

Truc Cong Ho ◽

Yeon-Jin Cho ◽

Jin-Seok Park ◽

...

Keyword(s):

Liver Injury ◽

Protective Effect ◽

Crassostrea Gigas ◽

Subcritical Water ◽

Ethanol Metabolism

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H2S in acute lung injury: a therapeutic dead end(?)

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00324-0 ◽

2020 ◽

Vol 8 (S1) ◽

Author(s):

Tamara Merz ◽

Nicole Denoix ◽

Martin Wepler ◽

Holger Gäßler ◽

David A. C. Messerer ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Acute Lung Injury ◽

Lung Injury ◽

Circulatory Shock ◽

Therapeutic Window ◽

Pharmacokinetics And Pharmacodynamics ◽

Clinical Reality ◽

Dead End

AbstractThis review addresses the plausibility of hydrogen sulfide (H2S) therapy for acute lung injury (ALI) and circulatory shock, by contrasting the promising preclinical results to the present clinical reality. The review discusses how the narrow therapeutic window and width, and potentially toxic effects, the route, dosing, and timing of administration all have to be balanced out very carefully. The development of standardized methods to determine in vitro and in vivo H2S concentrations, and the pharmacokinetics and pharmacodynamics of H2S-releasing compounds is a necessity to facilitate the safety of H2S-based therapies. We suggest the potential of exploiting already clinically approved compounds, which are known or unknown H2S donors, as a surrogate strategy.

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5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction

International Journal of Molecular Sciences ◽

10.3390/ijms22031083 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1083

Author(s):

Sukkum Ngullie Chang ◽

Se Ho Kim ◽

Debasish Kumar Dey ◽

Seon Min Park ◽

Omaima Nasif ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Elevated Serum ◽

In Vitro Study ◽

Biological Properties ◽

Autophagic Flux ◽

Serum Aminotransferase ◽

Ccl4 Treatment

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.

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Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

Cell Death and Disease ◽

10.1038/s41419-021-03980-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Lin Xu ◽

Xinge Zhang ◽

Yue Xin ◽

Jie Ma ◽

Chenyan Yang ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Steatosis ◽

Liver Steatosis ◽

Pharmacological Intervention ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Pathological Effect ◽

Mtorc1 Pathway

AbstractAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.

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