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

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.

References

  1. 1.

    Montalvo-Jave, E.E., T. Escalante-Tattersfield, J.A. Ortega-Salgado, E. Pina, and D.A. Geller. 2008. Factors in the pathophysiology of the liver ischemia-reperfusion injury. The Journal of Surgical Research 147: 153–159.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Li, C.X., K.T. Ng, Y. Shao, X.B. Liu, C.C. Ling, Y.Y. Ma, et al. 2014. The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response. Annals of Surgery 260: 317–328.

    PubMed  Article  Google Scholar 

  3. 3.

    Zhai, Y., R.W. Busuttil, and J.W. Kupiec-Weglinski. 2011. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 11: 1563–1569.

    CAS  Article  Google Scholar 

  4. 4.

    Cour, M., J. Loufouat, M. Paillard, L. Augeul, J. Goudable, M. Ovize, and L. Argaud. 2011. Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study. European Heart Journal 32: 226–235.

    PubMed  Article  Google Scholar 

  5. 5.

    Li, J., R.J. Li, G.Y. Lv, and H.Q. Liu. 2015. The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury. European Review for Medical and Pharmacological Sciences 19: 2036–2047.

    CAS  PubMed  Google Scholar 

  6. 6.

    Cannistra, M., M. Ruggiero, A. Zullo, G. Gallelli, S. Serafini, M. Maria, et al. 2016. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. International Journal of Surgery (London, England) 33 (Suppl 1): S57–S70.

    Article  Google Scholar 

  7. 7.

    Xi, J., M. Yan, S. Li, H. Song, L. Liu, Z. Shen, and J.Z. Cai. 2019. NOD1 activates autophagy to aggravate hepatic ischemia-reperfusion injury in mice. Journal of Cellular Biochemistry 120: 10605–10612.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Li, S.P., F.F. Wang, W.K. Zhang, M.Z. Bian, S.Y. Zhang, H. Yan, Y. Fang, and H.M. Zhang. 2019. Characteristics of changes in inflammatory cytokines as a function of hepatic ischemia-reperfusion Injury Stage in Mice. Inflammation 42: 2139–2147.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Wu, H.H., C.C. Huang, C.P. Chang, M.T. Lin, K.C. Niu, and Y.F. Tian. 2018. Heat Shock Protein 70 (HSP70) Reduces hepatic inflammatory and oxidative damage in a rat model of liver ischemia/reperfusion injury with hyperbaric oxygen preconditioning. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research 24: 8096–8104.

    CAS  Article  Google Scholar 

  10. 10.

    Ma, G., C. Chen, H. Jiang, Y. Qiu, Y. Li, X. Li, et al. 2017. Ribonuclease attenuates hepatic ischemia reperfusion induced cognitive impairment through the inhibition of inflammatory cytokines in aged mice. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 90: 62–68.

    CAS  Article  Google Scholar 

  11. 11.

    Colino, C.I., J.M. Lanao, and C. Gutierrez-Millan. 2020. Targeting of hepatic macrophages by therapeutic nanoparticles. Frontiers in Immunology 11: 218.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Krenkel, O., and F. Tacke. 2017. Liver macrophages in tissue homeostasis and disease. Nature Reviews Immunology 17: 306–321.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Ryter, S.W., and A.M. Choi. 2016. Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Translational Research : the Journal of Laboratory and Clinical Medicine 167: 7–34.

    CAS  Article  Google Scholar 

  14. 14.

    Fujisaki, N., K. Kohama, T. Nishimura, H. Yamashita, M. Ishikawa, A. Kanematsu, T. Yamada, S. Lee, T. Yumoto, K. Tsukahara, J. Kotani, and A. Nakao. 2016. Donor pretreatment with carbon monoxide prevents ischemia/reperfusion injury following heart transplantation in rats. Medical Gas Research 6: 122–129.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Cheng, Y., and J. Rong. 2017. Therapeutic potential of heme oxygenase-1/carbon monoxide system against ischemia-reperfusion Injury. Current Pharmaceutical Design 23: 3884–3898.

    CAS  PubMed  Google Scholar 

  16. 16.

    Otterbein, L.E., L.L. Mantell, and A.M. Choi. 1999. Carbon monoxide provides protection against hyperoxic lung injury. The American Journal of Physiology 276: L688–L694.

    CAS  PubMed  Google Scholar 

  17. 17.

    Sato, K., J. Balla, L. Otterbein, R.N. Smith, S. Brouard, Y. Lin, et al. 2001. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. Journal of Immunology (Baltimore, Md. : 1950) 166: 4185–4194.

    CAS  Article  Google Scholar 

  18. 18.

    Zhang, L.M., D.X. Zhang, L. Fu, Y. Li, X.P. Wang, M.M. Qi, C.C. Li, P.P. Song, X.D. Wang, and X.J. Kong. 2019. Carbon monoxide-releasing molecule-3 protects against cortical pyroptosis induced by hemorrhagic shock and resuscitation via mitochondrial regulation. Free Radical Biology & Medicine 141: 299–309.

    CAS  Article  Google Scholar 

  19. 19.

    Suzuki, S., L.H. Toledo-Pereyra, F.J. Rodriguez, and D. Cejalvo. 1993. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 55: 1265–1272.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Ke, B., X.D. Shen, F. Gao, S. Tsuchihashi, D.G. Farmer, D. Briscoe, R.W. Busuttil, and J.W. Kupiec-Weglinski. 2005. The CD154-CD40 T-cell co-stimulation pathway in liver ischemia and reperfusion inflammatory responses. Transplantation 79: 1078–1083.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Fu, L., D.X. Zhang, L.M. Zhang, Y.C. Song, F.H. Liu, Y. Li, X.P. Wang, W.C. Zheng, X.D. Wang, C.X. Gui, X.J. Kong, and L.Q. Kang. 2020. Exogenous carbon monoxide protects against mitochondrial DNA-induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation. International Journal of Molecular Medicine 45: 1176–1186.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zhang, L.M., and D.X. Zhang. 2019. The dual neuroprotective-neurotoxic effects of sevoflurane after hemorrhagic shock injury. The Journal of Surgical Research 235: 591–599.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Ye, Z., O. Chen, R. Zhang, A. Nakao, D. Fan, T. Zhang, et al. 2015. Methane attenuates hepatic ischemia/reperfusion injury in rats through antiapoptotic, anti-inflammatory, and antioxidative actions. Shock (Augusta, Ga) 44: 181–187.

    CAS  Article  Google Scholar 

  24. 24.

    Sordi, R., F. Chiazza, D. Collotta, G. Migliaretti, R.A. Colas, P. Vulliamy, K. Brohi, J. Dalli, M. Collino, and C. Thiemermann. 2019. Resolvin D1 attenuates the organ injury associated with experimental hemorrhagic shock. Annals of Surgery Publish Ahead of Print.

  25. 25.

    Schlegel, M., T. Granja, S. Kaiser, A. Korner, J. Henes, K. Konig, et al. 2014. Inhibition of neogenin dampens hepatic ischemia-reperfusion injury. Critical Care Medicine 42: e610–e619.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Zhang, X.J., X. Cheng, Z.Z. Yan, J. Fang, X. Wang, W. Wang, Z.Y. Liu, L.J. Shen, P. Zhang, P.X. Wang, R. Liao, Y.X. Ji, J.Y. Wang, S. Tian, X.Y. Zhu, Y. Zhang, R.F. Tian, L. Wang, X.L. Ma, Z. Huang, Z.G. She, and H. Li. 2018. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury. Nature Medicine 24: 73–83.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Xu, Y.J., L. Zheng, Y.W. Hu, and Q. Wang. 2018. Pyroptosis and its relationship to atherosclerosis. Clinica Chimica Acta; International Journal of Clinical Chemistry 476: 28–37.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Mulvihill, E., L. Sborgi, S.A. Mari, M. Pfreundschuh, S. Hiller, and D.J. Müller. 2018. Mechanism of membrane pore formation by human gasdermin-D. The EMBO Journal 37.

  29. 29.

    Man, S.M., R. Karki, and T.D. Kanneganti. 2017. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunological Reviews 277: 61–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Chen, X., W.T. He, L. Hu, J. Li, Y. Fang, X. Wang, X. Xu, Z. Wang, K. Huang, and J. Han. 2016. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Research 26: 1007–1020.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Shi, J., Y. Zhao, K. Wang, X. Shi, Y. Wang, H. Huang, Y. Zhuang, T. Cai, F. Wang, and F. Shao. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526: 660–665.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    He, W.T., H. Wan, L. Hu, P. Chen, X. Wang, Z. Huang, Z.H. Yang, C.Q. Zhong, and J. Han. 2015. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Research 25: 1285–1298.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Miao, E.A., J.V. Rajan, and A. Aderem. 2011. Caspase-1-induced pyroptotic cell death. Immunological Reviews 243: 206–214.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Qu, Y., H.L. Zhang, X.P. Zhang, and H.L. Jiang. 2018. Arachidonic acid attenuates brain damage in a rat model of ischemia/reperfusion by inhibiting inflammatory response and oxidative stress. Human & Experimental Toxicology 37: 135–141.

    CAS  Article  Google Scholar 

  35. 35.

    Chen, J., D.M. Zhang, X. Feng, J. Wang, Y.Y. Qin, T. Zhang, Q. Huang, R. Sheng, Z. Chen, M. Li, and Z.H. Qin. 2018. TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes. Neuropharmacology 131: 377–388.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Zhao, D., S.C. Deng, Y. Ma, Y.H. Hao, and Z.H. Jia. 2018. miR-221 alleviates the inflammatory response and cell apoptosis of neuronal cell through targeting TNFAIP2 in spinal cord ischemia-reperfusion. Neuroreport 29: 655–660.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Ma, Z., Z. Xin, W. Di, X. Yan, X. Li, R.J. Reiter, et al. 2017. Melatonin and mitochondrial function during ischemia/reperfusion injury. Cellular and Molecular Life Sciences: CMLS 74: 3989–3998.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Zhai, Y., H. Petrowsky, J.C. Hong, R.W. Busuttil, and J.W. Kupiec-Weglinski. 2013. Ischaemia-reperfusion injury in liver transplantation--from bench to bedside. Nature Reviews Gastroenterology & Hepatology 10: 79–89.

    CAS  Article  Google Scholar 

  39. 39.

    Li, J., J. Zhao, M. Xu, M. Li, B. Wang, X. Qu, C. Yu, H. Hang, Q. Xia, H. Wu, X. Sun, J. Gu, and X. Kong. 2020. Blocking GSDMD processing in innate immune cells but not in hepatocytes protects hepatic ischemia-reperfusion injury. Cell Death & Disease 11: 244.

    Article  CAS  Google Scholar 

  40. 40.

    Choi, E.Y., S.H. Choe, J.Y. Hyeon, J.I. Choi, I.S. Choi, and S.J. Kim. 2015. Carbon monoxide-releasing molecule-3 suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1beta in murine macrophages. European Journal of Pharmacology 764: 22–29.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Pizarro, M.D., J.V. Rodriguez, M.E. Mamprin, B.J. Fuller, B.E. Mann, R. Motterlini, and E.E. Guibert. 2009. Protective effects of a carbon monoxide-releasing molecule (CORM-3) during hepatic cold preservation. Cryobiology 58: 248–255.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Motterlini, R., and L.E. Otterbein. 2010. The therapeutic potential of carbon monoxide. Nature Reviews Drug Discovery 9: 728–743.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Ryter, S.W. 2019. Heme oxygenase-1/carbon monoxide as modulators of autophagy and inflammation. Archives of Biochemistry and Biophysics 678: 108186.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Ryter, S.W., K.C. Ma, and A.M.K. Choi. 2018. Carbon monoxide in lung cell physiology and disease. American Journal of Physiology. Cell Physiology 314: C211–c227.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Marazioti, A., M. Bucci, C. Coletta, V. Vellecco, P. Baskaran, C. Szabó, G. Cirino, A.R. Marques, B. Guerreiro, A.M.L. Gonçalves, J.D. Seixas, A. Beuve, C.C. Romão, and A. Papapetropoulos. 2011. Inhibition of nitric oxide-stimulated vasorelaxation by carbon monoxide-releasing molecules. Arteriosclerosis, Thrombosis, and Vascular Biology 31: 2570–2576.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Feng, S., D. Fox, and S.M. Man. 2018. Mechanisms of gasdermin family members in inflammasome signaling and cell death. Journal of Molecular Biology 430: 3068–3080.

    CAS  PubMed  Article  Google Scholar 

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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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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

Corresponding author

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 (2021). https://doi.org/10.1007/s10753-021-01419-w

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KEY WORDS

  • CORM-3
  • Ischemia/reperfusion injury
  • Pyroptosis
  • Kupffer cells
  • Liver