肝脏缺血再灌注损伤机制的研究进展
Research Progress on the Mechanism of Liver Ischemia Reperfusion Injury
DOI: 10.12677/acm.2025.1592661, PDF,   
作者: 杜文涛, 丁 毅*:新疆维吾尔自治区第六人民医院综合外科一病区,新疆 乌鲁木齐;何金玉:新疆维吾尔自治区第六人民医院心血管内科,新疆 乌鲁木齐
关键词: 肝脏缺血再灌注损伤保护机制发生机制Liver Ischemia Reperfusion Injury Protective Mechanism Mechanism of Occurrence
摘要: 缺血再灌注损伤是指组织或器官在缺血后紧接着得到血液供应,但是此时血液的供应却不利于缺血组织、器官的功能恢复,甚至加重了组织代谢的障碍、结构组织的破坏。肝脏缺血再灌注损伤是肝脏外科常见的病理生理现象,特别是肝脏移植和肝叶切除术后影响肝功能的一个重要原因。本文就肝脏缺血再灌注损伤发生机制简单作一综述。
Abstract: Ischemia reperfusion injury refers to the condition where tissues or organs receive blood supply immediately after ischemia, but this blood flow hinders functional recovery and may even exacerbate metabolic disorders and structural damage. Liver ischemia reperfusion injury is a common pathophysiological phenomenon in hepatobiliary surgery, particularly a major factor affecting liver function after liver transplantation and hepatic lobectomy. This article provides a concise review of the mechanisms underlying liver ischemia reperfusion injury.
文章引用:杜文涛, 何金玉, 丁毅. 肝脏缺血再灌注损伤机制的研究进展[J]. 临床医学进展, 2025, 15(9): 1605-1616. https://doi.org/10.12677/acm.2025.1592661

参考文献

[1] Lemasters, J.J. and Thurman, R.G. (1995) The Many Facets of Reperfusion Injury. Gastroenterology, 108, 1317-1320. [Google Scholar] [CrossRef] [PubMed]
[2] Li, J., Li, R.J., Lv, G.Y., et al. (2015) The Mechanisms and Strategies to Protect from Hepatic Ischemia Reperfusion Injury. European Review for Medical and Pharmacological Sciences, 19, 2036-2047.
[3] Papadimitriou, J.C., Phelps, P.C., Shin, M.L., Smith, M.W. and Trump, B.F. (1994) Effects of Ca2+ Deregulation on Mitochondrial Membrane Potential and Cell Viability in Nucleated Cells Following Lytic Complement Attack. Cell Calcium, 15, 217-227. [Google Scholar] [CrossRef] [PubMed]
[4] Anderson, C.D., Pierce, J., Nicoud, I., Belous, A., Knox, C.D. and Chari, R.S. (2005) Modulation of Mitochondrial Calcium Management Attenuates Hepatic Warm Ischemia-Reperfusion Injury. Liver Transplantation, 11, 663-668. [Google Scholar] [CrossRef] [PubMed]
[5] Liu, X. and Zhu, X.Z. (1999) Roles of P53, C-Myc, Bcl-2, Bax and Caspases in Serum Deprivation-Induced Neuronal Apoptosis: A Possible Neuroprotective Mechanism of Basic Fibroblast Growth Factor. NeuroReport, 10, 3087-3091. [Google Scholar] [CrossRef] [PubMed]
[6] Koo, A., Komatsu, H., Tao, G., Inoue, M., Guth, P.H. and Kaplowitz, N. (1992) Contribution of No-Reflow Phenomenon to Hepatic Injury after Ischemia-Reperfusion: Evidence for a Role for Superoxide Anion. Hepatology, 15, 507-514. [Google Scholar] [CrossRef] [PubMed]
[7] Klune, J.R. and Tsung, A. (2010) Molecular Biology of Liver Ischemia/Reperfusion Injury: Established Mechanisms and Recent Advancements. Surgical Clinics of North America, 90, 665-677. [Google Scholar] [CrossRef] [PubMed]
[8] Tsung, A., Sahai, R., Tanaka, H., Nakao, A., Fink, M.P., Lotze, M.T., et al. (2005) The Nuclear Factor HMGB1 Mediates Hepatic Injury after Murine Liver Ischemia-Reperfusion. The Journal of Experimental Medicine, 201, 1135-1143. [Google Scholar] [CrossRef] [PubMed]
[9] Cursio, R., Colosetti, P. and Gugenheim, J. (2015) Autophagy and Liver Ischemia-Reperfusion Injury. BioMed Research International, 2015, Article ID: 417590. [Google Scholar] [CrossRef] [PubMed]
[10] Chouchani, E.T., Pell, V.R., James, A.M., Work, L.M., Saeb-Parsy, K., Frezza, C., et al. (2016) A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metabolism, 23, 254-263. [Google Scholar] [CrossRef] [PubMed]
[11] Reddy, N.M., Kleeberger, S.R., Kensler, T.W., Yamamoto, M., Hassoun, P.M. and Reddy, S.P. (2017) Correction: Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice. The Journal of Immunology, 198, Article No. 3755. [Google Scholar] [CrossRef] [PubMed]
[12] Huang, J., Yue, S., Ke, B., Zhu, J., Shen, X., Zhai, Y., et al. (2014) Nuclear Factor Erythroid 2-Related Factor 2 Regulates Toll-Like Receptor 4 Innate Responses in Mouse Liver Ischemia-Reperfusion Injury through Akt-Forkhead Box Protein O1 Signaling Network. Transplantation, 98, 721-728. [Google Scholar] [CrossRef] [PubMed]
[13] Bahde, R. and Spiegel, H. (2010) Hepatic Ischaemia-Reperfusion Injury from Bench to Bedside. British Journal of Surgery, 97, 1461-1475. [Google Scholar] [CrossRef] [PubMed]
[14] Jaeschke, H. (2011) Reactive Oxygen and Mechanisms of Inflammatory Liver Injury: Present Concepts. Journal of Gastroenterology and Hepatology, 26, 173-179. [Google Scholar] [CrossRef] [PubMed]
[15] Hide, D., Ortega-Ribera, M., Garcia-Pagan, J., Peralta, C., Bosch, J. and Gracia-Sancho, J. (2016) Effects of Warm Ischemia and Reperfusion on the Liver Microcirculatory Phenotype of Rats: Underlying Mechanisms and Pharmacological Therapy. Scientific Reports, 6, Article No. 22107. [Google Scholar] [CrossRef] [PubMed]
[16] Csak, T., Velayudham, A., Hritz, I., Petrasek, J., Levin, I., Lippai, D., et al. (2011) Deficiency in Myeloid Differentiation Factor-2 and Toll-Like Receptor 4 Expression Attenuates Nonalcoholic Steatohepatitis and Fibrosis in Mice. American Journal of Physiology-Gastrointestinal and Liver Physiology, 300, G433-G441. [Google Scholar] [CrossRef] [PubMed]
[17] Nayak, L., Lin, Z. and Jain, M.K. (2011) “Go with the Flow”: How Krüppel-Like Factor 2 Regulates the Vasoprotective Effects of Shear Stress. Antioxidants & Redox Signaling, 15, 1449-1461. [Google Scholar] [CrossRef] [PubMed]
[18] Gracia-Sancho, J., Villarreal, G., Zhang, Y., Yu, J.X., Liu, Y., Tullius, S.G., et al. (2010) Flow Cessation Triggers Endothelial Dysfunction during Organ Cold Storage Conditions: Strategies for Pharmacologic Intervention. Transplantation, 90, 142-149. [Google Scholar] [CrossRef] [PubMed]
[19] Montalvo-Jave, E.E., Escalante-Tattersfield, T., Ortega-Salgado, J.A., Piña, E. and Geller, D.A. (2008) Factors in the Pathophysiology of the Liver Ischemia-Reperfusion Injury. Journal of Surgical Research, 147, 153-159. [Google Scholar] [CrossRef] [PubMed]
[20] Rentsch, M., Post, S., Palma, P., Lang, G., Menger, M.D. and Messmer, K. (2000) Anti-ICAM-1 Blockade Reduces Postsinusoidal WBC Adherence Following Cold Ischemia and Reperfusion, but Does Not Improve Early Graft Function in Rat Liver Transplantation. Journal of Hepatology, 32, 821-828. [Google Scholar] [CrossRef] [PubMed]
[21] Jaeschke, H. (2003) Molecular Mechanisms of Hepatic Ischemia-Reperfusion Injury and Preconditioning. American Journal of Physiology-Gastrointestinal and Liver Physiology, 284, G15-G26. [Google Scholar] [CrossRef] [PubMed]
[22] Heemann, U.W., Tullius, S.G., Azuma, H., Kupiec-Weglinsky, J. and Tilney, N.L. (1994) Adhesion Molecules and Transplantation. Annals of Surgery, 219, 4-12. [Google Scholar] [CrossRef] [PubMed]
[23] Kuzume, M., Nakano, H., Yamaguchi, M., Matsumiya, A., Shimokohbe, G., Kitamura, N., et al. (1997) A Monoclonal Antibody against ICAM-1 Suppresses Hepatic Ischemia-Reperfusion Injury in Rats. European Surgical Research, 29, 93-100. [Google Scholar] [CrossRef] [PubMed]
[24] Wang, Z., et al. (2007) Protection of Veratrum nigrum L. var. Ussuriense Nakai Alkaloids against ischemia-Reperfusion Injury of the Rat Liver. World Journal of Gastroenterology, 13, 564-571.
[25] Nakano, H., Nagasaki, H., Yoshida, K., Kigawa, G., Fujiwara, Y., Kitamura, N., et al. (1998) N-acetylcysteine and Anti-ICAM-1 Monoclonal Antibody Reduce Ischemia-Reperfusion Injury of the Steatotic Rat Liver. Transplantation Proceedings, 30, Article No. 3763. [Google Scholar] [CrossRef] [PubMed]
[26] Nery, J.R., Weppler, D., Olson, L., Fragulidis, G.P., Khan, M.F., Webb, M.G., et al. (1997) Donor Infection and Primary Nonfunction in Liver Transplantation. Transplantation Proceedings, 29, 481-483. [Google Scholar] [CrossRef] [PubMed]
[27] Kielian, T.L. and Blecha, F. (1995) CD14 and Other Recognition Molecules for Lipopolysaccharide: A Review. Immunopharmacology, 29, 187-205. [Google Scholar] [CrossRef] [PubMed]
[28] Kobayashi, H., Nonami, T., Kurokawa, T., Sugiyama, S., Ozawa, T. and Takagi, H. (1991) Mechanism and Prevention of Ischemia-Reperfusion-Induced Liver Injury in Rats. Journal of Surgical Research, 51, 240-244. [Google Scholar] [CrossRef] [PubMed]
[29] Tan, S., Yokoyama, Y., Dickens, E., Cash, T.G., Freeman, B.A. and Parks, D.A. (1993) Xanthine Oxidase Activity in the Circulation of Rats Following Hemorrhagic Shock. Free Radical Biology and Medicine, 15, 407-414. [Google Scholar] [CrossRef] [PubMed]
[30] Nagai, S., Asoh, S., Kobayashi, Y., Shidara, Y., Mori, T., Suzuki, M., et al. (2007) Protection of Hepatic Cells from Apoptosis Induced by Ischemia/reperfusion Injury by Protein Therapeutics. Hepatology Research, 37, 133-142. [Google Scholar] [CrossRef] [PubMed]
[31] Kohli, V., Selzner, M., Madden, J.F., Bentley, R.C. and Clavien, P. (1999) Endothelial Cell and Hepatocyte Deaths Occur by Apoptosis after Ischemia-Reperfusion Injury in the Rat Liver. Transplantation, 67, 1099-1105. [Google Scholar] [CrossRef] [PubMed]
[32] Menger, M.D., Richter, S., Yamauchi, J., et al. (1999) Role of Microcirculation in Hepatic Ischemia/Reperfusion Inju-ry. Hepatogastroenterology, 46, 1452-1457.
[33] 原金红, 马茂, 马振华. 乌司他丁对大鼠肝脏缺血再灌注损伤治疗作用的研究[J]. 陕西医学杂志, 2007, 36(9): 1134-1136.
[34] Andrej, K., Georg, E., Peter, B., et al. (2002) Dose-Dependent Effect of Propofol on Regional Splanchnic Blood Flow during Lower Abdominal Surgery. American Journal of Physiology-Gastrointestinal and Liver Physiology, 283, 553-560.
[35] Bacon, K.B., Premack, B.A., Gardner, P. and Schall, T.J. (1995) Activation of Dual T Cell Signaling Pathways by the Chemokine Rantes. Science, 269, 1727-1730. [Google Scholar] [CrossRef] [PubMed]
[36] Martin, M., Mory, C., Prescher, A., Wittekind, C., Fiedler, M. and Uhlmann, D. (2010) Protective Effects of Early CD4+ T Cell Reduction in Hepatic Ischemia/reperfusion Injury. Journal of Gastrointestinal Surgery, 14, 511-519. [Google Scholar] [CrossRef] [PubMed]
[37] Kuboki, S., Sakai, N., Tschöp, J., Edwards, M.J., Lentsch, A.B. and Caldwell, C.C. (2009) Distinct Contributions of CD4+ T Cell Subsets in Hepatic Ischemia/reperfusion Injury. American Journal of Physiology-Gastrointestinal and Liver Physiology, 296, G1054-G1059. [Google Scholar] [CrossRef] [PubMed]
[38] Kim, H., Park, K., Yoo, E., Kim, Y., Kim, Y., Kim, H., et al. (2007) Effects of PGC-1alpha on TNF-alpha Induced MCP-1 and VCAM-1 Expression and NF-kappaB Activation in Humanaortic Smooth Muscle and Endothelial Cells. Antioxidants & Redox Signaling, 9, 301-307. [Google Scholar] [CrossRef] [PubMed]
[39] Lee, C., Miura, K., Liu, X. and Zweier, J.L. (2000) Biphasic Regulation of Leukocyte Superoxide Generation by Nitric Oxide and Peroxynitrite. Journal of Biological Chemistry, 275, 38965-38972. [Google Scholar] [CrossRef] [PubMed]
[40] Dikalova, A.E., Bikineyeva, A.T., Budzyn, K., Nazarewicz, R.R., McCann, L., Lewis, W., et al. (2010) Therapeutic Targeting of Mitochondrial Superoxide in Hypertension. Circulation Research, 107, 106-116. [Google Scholar] [CrossRef] [PubMed]
[41] Ohashi, M., Runge, M.S., Faraci, F.M. and Heistad, D.D. (2006) MnSOD Deficiency Increases Endothelial Dysfunction in AooE-Deficient Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2331-2336. [Google Scholar] [CrossRef] [PubMed]
[42] 何其宽, 戴宁高, 叶瑞凡, 等. 干细胞来源外泌体对大鼠肝脏缺血再灌注损伤的保护作用[J]. 肝胆胰外科杂志, 2018(2): 134-141.
[43] Marshall, K.M., He, S., Zhong, Z., Atkinson, C. and Tomlinson, S. (2014) Dissecting the Complement Pathway in Hepatic Injury and Regeneration with a Novel Protective Strategy. Journal of Experimental Medicine, 211, 1793-1805. [Google Scholar] [CrossRef] [PubMed]
[44] Saidi, R.F., Rajeshkumar, B., Shariftabrizi, A., Dresser, K. and Walter, O. (2014) Human C1 Inhibitor Attenuates Liver Ischemia-Reperfusion Injury and Promotes Liver Regeneration. Journal of Surgical Research, 187, 660-666. [Google Scholar] [CrossRef] [PubMed]
[45] Nikoletopoulou, V., Markaki, M., Palikaras, K. and Tavernarakis, N. (2013) Crosstalk between Apoptosis, Necrosis and Autophagy. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1833, 3448-3459. [Google Scholar] [CrossRef] [PubMed]
[46] Shen, M., Lu, J., Dai, W., Wang, F., Xu, L., Chen, K., et al. (2013) Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy. Mediators of Inflammation, 2013, 2409-2420. [Google Scholar] [CrossRef] [PubMed]
[47] Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., et al. (2011) Autophagy-Deficient Mice Develop Multiple Liver Tumors. Genes & Development, 25, 795-800. [Google Scholar] [CrossRef] [PubMed]
[48] Qiao, P. (2015) Heat Shock Pretreatment Improves Stem Cell Repair Following Ischemia-Reperfusion Injury via Autophagy. World Journal of Gastroenterology, 21, Article No. 12822. [Google Scholar] [CrossRef] [PubMed]
[49] Li, J., Wang, F., Xia, Y., Dai, W., Chen, K., Li, S., et al. (2015) Astaxanthin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy via the ROS/MAPK Pathway in Mice. Marine Drugs, 13, 3368-3387. [Google Scholar] [CrossRef] [PubMed]
[50] Boya, P., Reggiori, F. and Codogno, P. (2013) Emerging Regulation and Functions of Autophagy. Nature Cell Biology, 15, 713-720. [Google Scholar] [CrossRef] [PubMed]
[51] Cheng, P., Wang, F., Chen, K., Shen, M., Dai, W., Xu, L., et al. (2014) Hydrogen Sulfide Ameliorates Ischemia/Reperfusion-Induced Hepatitis by Inhibiting Apoptosis and Autophagy Pathways. Mediators of Inflammation, 2014, Article ID: 935251. [Google Scholar] [CrossRef] [PubMed]
[52] Kim, J., Nitta, T., Mohuczy, D., O'Malley, K.A., Moldawer, L.L., Dunn, W.A., et al. (2008) Impaired Autophagy: A Mechanism of Mitochondrial Dysfunction in Anoxic Rat Hepatocytes. Hepatology, 47, 1725-1736. [Google Scholar] [CrossRef] [PubMed]
[53] Elmore, S.P., Qian, T., Grissom, S.F. and Lemasters, J.J. (2001) The Mitochondrial Permeability Transition Initiates Autophagy in Rat Hepatocytes. The FASEB Journal, 15, 2286-2287. [Google Scholar] [CrossRef] [PubMed]
[54] Bilbao, G., Contreras, J.L., Eckhoff, D.E., Mikheeva, G., Krasnykh, V., Douglas, J.T., et al. (1999) Reduction of Ischemia-Reperfusion Injury of the Liver by in Vivo Adenovirus-Mediated Gene Transfer of the Antiapoptotic Bcl-2 Gene. Annals of Surgery, 230, 185-193. [Google Scholar] [CrossRef] [PubMed]
[55] Barrier, A., Olaya, N., Chiappini, F., Roser, F., Scatton, O., Artus, C., et al. (2005) Ischemic Preconditioning Modulates the Expression of Several Genes, Leading to the Overproduction of IL-1Ra, iNOS, and Bcl‐2 in a Human Model of Liver Ischemia‐Reperfusion. The FASEB Journal, 19, 1617-1626. [Google Scholar] [CrossRef] [PubMed]
[56] Yan, R., Li, Y., Zhang, L., Xia, N., Liu, Q., Sun, H., et al. (2015) Augmenter of Liver Regeneration Attenuates Inflammation of Renal Ischemia/reperfusion Injury through the NF-KappaB Pathway in Rats. International Urology and Nephrology, 47, 861-868. [Google Scholar] [CrossRef] [PubMed]
[57] Chen, A.C., Arany, P.R., Huang, Y., Tomkinson, E.M., Sharma, S.K., Kharkwal, G.B., et al. (2011) Low-Level Laser Therapy Activates NF-κB via Generation of Reactive Oxygen Species in Mouse Embryonic Fibroblasts. PLOS ONE, 6, e22453. [Google Scholar] [CrossRef] [PubMed]
[58] Jiang, W., Kong, L., Ni, Q., Lu, Y., Ding, W., Liu, G., et al. (2014) MiR-146a Ameliorates Liver Ischemia/Reperfusion Injury by Suppressing IRAK1 and Traf6. PLOS ONE, 9, e101530. [Google Scholar] [CrossRef] [PubMed]
[59] Hernandez-Alejandro, R., Zhang, X., Croome, K.P., Zheng, X., Parfitt, J., Chen, D., et al. (2012) Reduction of Liver Ischemia Reperfusion Injury by Silencing of TNF-α Gene with shRNA. Journal of Surgical Research, 176, 614-620. [Google Scholar] [CrossRef] [PubMed]
[60] Huang, X., Gao, Y., Qin, J. and Lu, S. (2014) The Role of Mir-34a in the Hepatoprotective Effect of Hydrogen Sulfide on Ischemia/Reperfusion Injury in Young and Old Rats. PLOS ONE, 9, e113305. [Google Scholar] [CrossRef] [PubMed]
[61] Chen, Z., Jia, S., Li, D., Cai, J., Tu, J., Geng, B., et al. (2013) Silencing of Long Noncoding RNA AK139328 Attenuates Ischemia/Reperfusion Injury in Mouse Livers. PLOS ONE, 8, e80817. [Google Scholar] [CrossRef] [PubMed]