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Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver

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Abstract

Background and purpose

Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism.

Methods

Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion. The liver and serum were collected 3, 6, and 24 h after reperfusion.

Results

In the NaHS(−) group, severe IRI was apparent by the ALT leakage, tissue injury score, apoptosis, lipid peroxidation, and inflammation (higher plasma TNF-α, IL-6, IL-1β, IFN-γ, IL-23, IL-17, and CD40L), whereas IRI was significantly ameliorated in the NaHS(+) group. These effects could be explained by the augmented nuclear translocation of Nrf2, and the resulting up-regulation of HO-1 and thioredoxin-1. Phosphorylation of the PDK-1/Akt/mTOR/p70S6k axis, which is known to mediate pro-survival and anti-apoptotic signals, was significantly augmented in the NaHS(+) group, with a higher rate of PCNA-positive cells thereafter.

Conclusion

NaHS ameliorated hepatic IRI by direct and indirect anti-oxidant activities by augmenting pro-survival, anti-apoptotic, and anti-inflammatory signals via mechanisms involving Nrf-2, and by accelerating hepatic regeneration via mechanisms involving Akt-p70S6k.

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Abbreviations

ALT:

Alanine aminotransferase

CO:

Carbon monoxide

DCD:

Donation after cardiac death

ELISA:

Enzyme-linked immunosorbent assay

ER:

Endoplasmic reticulum

GSH:

Glutathione

4-HNE:

4-hydroxy-2-nonenal

HO-1:

Heme oxygenase 1

TRX-1:

Thioredoxin-1

HPFs:

High-power fields

H2S:

Hydrogen sulfide

HSPs:

Heat shock proteins

IL-6:

Interleukin 6

I/R:

Ischemia and reperfusion

IRI:

Ischemia and reperfusion injury

Keap-1:

Kelch-like ECH-associated protein 1

MDA:

Malondialdehyde

MPT:

Mitochondrial permeability transition

mTOR:

Mammalian target of rapamycin

NaHS:

Sodium hydrogen sulfide

NF-kappaB:

Nuclear factor-kappa B

Nrf2:

NF-E2-related factor 2

PDK-1:

Phosphoinositide-dependent kinase 1

PI3K:

Phosphoinositide 3 kinase

PKC:

Protein kinase C

PNF:

Primary graft non-function

PVDF:

Polyvinylidene difluoride

p70s6k:

70-kDa Ribosomal protein S6 kinase

ROS:

Reactive oxygen species

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

STAT3:

Signal transducer and activator of transcription 3

TNF-α:

Tumor necrosis factor α

TRX-1:

Thioredoxin 1

TUNEL:

Terminal dUTP nick end-labeling

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Acknowledgments

We thank Mr. Masatoshi Horigome and Ms. Sayaka Miyoshi for their excellent technical support. This work was supported in part by a Public Trust Surgery Fund (2012) and a grant-in aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (No. 25293272).

Conflict of interest

Shingo Shimada and his co-authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Shingo Shimada, Kenji Wakayama, Takahisa Ishikawa, Nozomi Kobayashi, Toshiya Kamiyama & Akinobu Taketomi

  2. Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Moto Fukai & Kenichiro Yamashita

  3. Department of Pathology, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Taichi Kimura

  4. Department of Organ Transplantation, Central Clinical Facilities, Hokkaido University Hospital, N-14, W-5, Kita-ku, Sapporo, Japan

    Tsuyoshi Shimamura

  5. St. Maria Hospital affiliated Laboratory, Tsubukuhonmachi 422, Kurume, Japan

    Satoru Todo

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  1. Shingo Shimada
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  2. Moto Fukai
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Correspondence to Moto Fukai.

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Shimada, S., Fukai, M., Wakayama, K. et al. Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. Surg Today 45, 892–903 (2015). https://doi.org/10.1007/s00595-014-1064-4

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  • DOI: https://doi.org/10.1007/s00595-014-1064-4

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