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Carbon Monoxide–Releasing Molecule-3 Alleviates Kupffer Cell Pyroptosis Induced by Hemorrhagic Shock and Resuscitation via sGC-cGMP Signal Pathway

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Abstract

Following hepatic ischemia-reperfusion injury, Kupffer cells could be activated by inflammatory factors released from damaged hepatocytes. Carbon monoxide (CO)-releasing molecule (CORM)-3, a water-soluble transition metal carbonyl, exhibits excellent anti-inflammatory and anti-pyroptosis properties. We investigated whether CORM-3 attenuated hemorrhagic shock and resuscitation (HSR)-induced pyroptosis of Kupffer cells through the soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal pathway. NS2028 (10 mg/kg), a blocker of sGC, was administrated at the onset of hemorrhage, but CORM-3 (4 mg/kg) was infused after resuscitation via femoral vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, tumor necrosis Factor-α (TNF-α), and interleukin-1β (IL-1β) were measured at 3, 6, 12, and 24 h after HSR, respectively. Six hours post-HSR, liver injury, pyroptosis of Kupffer cells, and expressions in total caspase-1, cleaved caspase-1, gasdermin D (GSDMD) N-terminal fragment, IL-1β, and IL-18 were measured by hematoxylin-eosin (H&E), immunofluorescence and western blot assays, respectively (Fig. 1). The rats exposed to HSR exhibited significant upregulated levels of serum ALT, AST, TNF-α, and IL-1β, elevated liver injury score, increased pyroptosis of Kupffer cells, and accumulated expressions of pyroptosis-associated protein including cleaved caspase-1, GSDMD N-terminal fragment, IL-1β, and IL-18 than sham-treated rats. However, CORM-3 administration markedly reduced liver injury and pyroptosis of Kupffer cells, whereas these protective effects could be partially blocked by NS2028. CORM-3 can mitigate pyroptosis of Kupffer cells in a blood loss and re-infusion model of rats via sGC-cGMP signal pathway.

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Data Availability

The data used to support the findings of the present study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors express their gratitude to Yu-Lin Chang from Cangzhou Central Hospital who helped us with technical support.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81701296 by Dr. Li-Min Zhang).

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Authors and Affiliations

  1. Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China

    Xu-Peng Wang, Yang Bai, Yan Li, Yu-Lin Chang & Li-Min Zhang

  2. Department of Anesthesiology, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China

    Wei-Chao Zheng, Yue Xin & Yu-Lin Chang

  3. Department of Neurosurgery, Cangzhou Central Hospital, Hebei Medical University, Cangzhou, China

    Jing-Zhou Wang

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Contributions

Design of the study: Li-Min Zhang

Editing the manuscript: Xu-Peng Wang, Wei-Chao Zheng, and Li-Min Zhang

Statistical analysis: Xu-Peng Wang, Wei-Chao Zheng, and Li-Min Zhang

Experiment and data collection: Xu-Peng Wang, Wei-Chao Zheng, Yue Xin, Yang Bai, Yan Li, Jing-Zhou Wang, and Yu-Lin Chang

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Correspondence to Li-Min Zhang.

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All animal experiments were carried out in accordance with the National Institute of Health Guideline for the Care and Use of Laboratory Animals and approved by the Animal Review Board of Cangzhou Central Hospital.

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Wang, XP., Zheng, WC., Bai, Y. et al. Carbon Monoxide–Releasing Molecule-3 Alleviates Kupffer Cell Pyroptosis Induced by Hemorrhagic Shock and Resuscitation via sGC-cGMP Signal Pathway. Inflammation 44, 1330–1344 (2021). https://doi.org/10.1007/s10753-021-01419-w

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