|
|
系统性炎症反应介导慢加急性肝衰竭的研究进展
|
Abstract:
慢加急性肝衰竭(ACLF)指慢性肝病急剧恶化并出现功能障碍，是一种伴有肝内外器官衰竭、短期预后不佳的严重临床综合征。虽然目前发病机制尚未完全阐明，但可以明确系统性炎症反应与ACLF的起病和进展具有密切的关联。细菌感染、过量的酒精摄入以及嗜肝病毒活动可以释放病原相关分子模式和/或损伤相关分子模式激活炎症反应，损害重要脏器功能，诱导ACLF发生。疾病晚期由于炎症反应持续存在，先天性免疫细胞功能受抑难以抵御再发感染，病死率进一步升高。同时反应产生的炎性介质还将阻碍肝脏修复、改变血流动力学及线粒体功能加剧器官损伤。白介素22、间充质干细胞等新现的治疗方式可以改善炎症反应、降低感染风险、延缓病情进展，为部分患者后续接受肝移植治疗争取更多时间。针对系统性炎症作用于ACLF的诸多环节还有待进一步研究，开发更加有效的抗炎治疗手段也将提高患者生存率并缓解疾病负担。
Acute-on-chronic liver failure (ACLF) is delineated as a rapid exacerbation of chronic hepatic disorders, culminating in functional impairment and is identified as a grave clinical syndrome characterized by both hepatic and extrahepatic organ failures, concomitant with a dismal short-term prognosis. The pathogenesis of ACLF, albeit not entirely elucidated, has been unequivocally associated with systemic inflammatory playing a pivotal role in its initiation and progression. The release of pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) triggered by bacterial infections, excessive alcohol consumption, and active hepatotropic viral infections activates inflammatory responses. This, in turn, inflicts damage upon major organs function, precipitating the onset of ACLF. In the advanced stages of the disease, the protracted presence of inflammatory responses leads to a suppression of innate immune cell functions, thereby impairing the host’s defense against recurrent infections and further escalating mortality rates. Concurrently, the inflammatory mediators impede hepatic regeneration, modify hemodynamics, and deteriorate mitochondrial function, thus exacerbating organ damage. Emerging therapeutic interventions, such as the administration of interleukin-22 and the employment of mesenchymal stem cells, have shown promise in ameliorating the inflammatory response, diminishing infection risks, and retarding disease progression, thereby extending the temporal window for potential liver transplantation in a subset of patients. The intricate involvement of systemic inflammation in the multifaceted progression of ACLF necessitates further investigation, with the aim of developing more efficacious anti-inflammatory therapeutic modalities to enhance patient survival rates and alleviate disease burden.
| [1] | Ohnishi, H., Sugihara, J., Moriwaki, H., et al. (1995) [Acute-on-Chronic Liver Failure]. Ryoikibetsu Shokogun Shirizu, No. 7, 217-219. |
| [2] | Moreau, R., Jalan, R., Gines, P., et al. (2013) Acute-on-Chronic Liver Failure Is a Distinct Syndrome that Develops in Patients with Acute Decompensation of Cirrhosis. Gastroenterology, 144, 1426-1437. https://doi.org/10.1053/j.gastro.2013.02.042 |
| [3] | Arroyo, V., Moreau, R. and Jalan, R. (2020) Acute-on-Chronic Liver Failure. The New England Journal of Medicine, 382, 2137-2145. https://doi.org/10.1056/NEJMra1914900 |
| [4] | Verstak, B., Nagpal, K., Bottomley, S.P., et al. (2009) MyD88 Adapter-Like (Mal)/TIRAP Interaction with TRAF6 Is Critical for TLR2-and TLR4-Mediated NF-KappaB Proinflammatory Responses. The Journal of Biological Chemistry, 284, 24192-24203. https://doi.org/10.1074/jbc.M109.023044 |
| [5] | Kayagaki, N., Wong, M.T., Stowe, I.B., et al. (2013) Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4. Science, 341, 1246-1249. https://doi.org/10.1126/science.1240248 |
| [6] | Shi, J., Zhao, Y., Wang, Y., et al. (2014) Inflammatory Caspases Are Innate Immune Receptors for Intracellular LPS. Nature, 514, 187-192. https://doi.org/10.1038/nature13683 |
| [7] | Elias, G., Schonfeld, M., Saleh, S., et al. (2023) Sepsis-Induced Endothelial Dysfunction Drives Acute-on-Chronic Liver Failure through Angiopoietin-2-HGF-C/EBPbeta Pathway. Hepatology, 78, 803-819. https://doi.org/10.1097/HEP.0000000000000354 |
| [8] | Dominguez, M., Miquel, R., Colmenero, J., et al. (2009) Hepatic Expression of CXC Chemokines Predicts Portal Hypertension and Survival in Patients with Alcoholic Hepatitis. Gastroenterology, 136, 1639-1650. https://doi.org/10.1053/j.gastro.2009.01.056 |
| [9] | Sarin, S.K., Pande, A. and Schnabl, B. (2019) Microbiome as a Therapeutic Target in Alcohol-Related Liver Disease. Journal of Hepatology, 70, 260-272. https://doi.org/10.1016/j.jhep.2018.10.019 |
| [10] | Gustot, T. and Jalan, R. (2019) Acute-on-Chronic Liver Failure in Patients with Alcohol-Related Liver Disease. Journal of Hepatology, 70, 319-327. https://doi.org/10.1016/j.jhep.2018.12.008 |
| [11] | Kim, Y.S. and Kim, S.G. (2020) Endoplasmic Reticulum Stress and Autophagy Dysregulation in Alcoholic and Non-Alcoholic Liver Diseases. Clinical and Molecular Hepatology, 26, 715-727. https://doi.org/10.3350/cmh.2020.0173 |
| [12] | Dubuquoy, L., Louvet, A., Lassailly, G., et al. (2015) Progenitor Cell Expansion and Impaired Hepatocyte Regeneration in Explanted Livers from Alcoholic Hepatitis. Gut, 64, 1949-1960. https://doi.org/10.1136/gutjnl-2014-308410 |
| [13] | Bhatti, T.K., Singal, A.K. and Kwo, P.Y. (2023) Viral Hepatitis and Acute-on-Chronic Liver Failure. Clinics in Liver Disease, 27, 617-630. https://doi.org/10.1016/j.cld.2023.03.006 |
| [14] | Zhang, X., Zhang, Y., Zhou, P., et al. (2022) Down-Regulated Cylindromatosis Enhances NF-KappaB Activation and Aggravates Inflammation in HBV-ACLF Patients. Emerging Microbes & Infections, 11, 1586-1601. https://doi.org/10.1080/22221751.2022.2077128 |
| [15] | Zhou, C., Zhang, N., He, T.T., et al. (2020) High Levels of Serum Interleukin-6 Increase Mortality of Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure. World Journal of Gastroenterology, 26, 4479-4488. https://doi.org/10.3748/wjg.v26.i30.4479 |
| [16] | Zhu, B., Gao, F., Li, Y., et al. (2023) Serum Cytokine and Chemokine Profiles and Disease Prognosis in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure. Frontiers in Immunology, 14, Article 1133656. https://doi.org/10.3389/fimmu.2023.1133656 |
| [17] | Martin-Mateos, R., Alvarez-Mon, M. and Albillos, A. (2019) Dysfunctional Immune Response in Acute-on-Chronic Liver Failure: It Takes Two to Tango. Frontiers in Immunology, 10, Article 973. https://doi.org/10.3389/fimmu.2019.00973 |
| [18] | Zaccherini, G., Weiss, E. and Moreau, R. (2021) Acute-on-Chronic Liver Failure: Definitions, Pathophysiology and Principles of Treatment. JHEP Reports: Innovation in Hepatology, 3, Article 100176. https://doi.org/10.1016/j.jhepr.2020.100176 |
| [19] | Iwasaki, A. and Medzhitov, R. (2015) Control of Adaptive Immunity by the Innate Immune System. Nature Immunology, 16, 343-353. https://doi.org/10.1038/ni.3123 |
| [20] | Wu, J. and Chen, Z.J. (2014) Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids. Annual Review of Immunology, 32, 461-488. https://doi.org/10.1146/annurev-immunol-032713-120156 |
| [21] | Albillos, A., De Gottardi, A. and Rescigno, M. (2020) The Gut-Liver Axis in Liver Disease: Pathophysiological Basis for Therapy. Journal of Hepatology, 72, 558-577. https://doi.org/10.1016/j.jhep.2019.10.003 |
| [22] | Arroyo, V., Angeli, P., Moreau, R., et al. (2021) The Systemic Inflammation Hypothesis: Towards a New Paradigm of Acute Decompensation and Multiorgan Failure in Cirrhosis. Journal of Hepatology, 74, 670-685. https://doi.org/10.1016/j.jhep.2020.11.048 |
| [23] | Kou, K., Sun, X., Tian, G., et al. (2022) The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing. Journal of Immunology Research, 2022, Article ID: 5091275. https://doi.org/10.1155/2022/5091275 |
| [24] | Xu, H., Yang, J., Gao, W., et al. (2014) Innate Immune Sensing of Bacterial Modifications of Rho GTPases by the Pyrin Inflammasome. Nature, 513, 237-241. https://doi.org/10.1038/nature13449 |
| [25] | Bianchi, M.E. (2007) DAMPs, PAMPs and Alarmins: All We Need to Know about Danger. Journal of Leukocyte Biology, 81, 1-5. https://doi.org/10.1189/jlb.0306164 |
| [26] | Wang, Y., Zhang, H., Chen, Q., et al. (2020) TNF-α/HMGB1 Inflammation Signalling Pathway Regulates Pyroptosis during Liver Failure and Acute Kidney Injury. Cell Proliferation, 53, e12829. https://doi.org/10.1111/cpr.12829 |
| [27] | Murao, A., Aziz, M., Wang, H., et al. (2021) Release Mechanisms of Major DAMPs. Apoptosis: An International Journal on Programmed Cell Death, 26, 152-162. https://doi.org/10.1007/s10495-021-01663-3 |
| [28] | Clària, J., Stauber, R.E., Coenraad, M.J., et al. (2016) Systemic Inflammation in Decompensated Cirrhosis: Characterization and Role in Acute-on-Chronic Liver Failure. Hepatology, 64, 1249-1264. https://doi.org/10.1002/hep.28740 |
| [29] | Engelmann, C., Zhang, I.W. and Claria, J. (2023) Mechanisms of Immunity in Acutely Decompensated Cirrhosis and Acute-on-Chronic Liver Failure. Liver International. https://doi.org/10.1111/liv.15644 |
| [30] | Bernardi, M., Moreau, R., Angeli, P., et al. (2015) Mechanisms of Decompensation and Organ Failure in Cirrhosis: From Peripheral Arterial Vasodilation to Systemic Inflammation Hypothesis. Journal of Hepatology, 63, 1272-1284. https://doi.org/10.1016/j.jhep.2015.07.004 |
| [31] | Triantafyllou, E., Woollard, K.J., McPhail, M.J.W., et al. (2018) The Role of Monocytes and Macrophages in Acute and Acute-on-Chronic Liver Failure. Frontiers in Immunology, 9, Article 2948. https://doi.org/10.3389/fimmu.2018.02948 |
| [32] | Bernsmeier, C., Triantafyllou, E., Brenig, R., et al. (2018) CD14 CD15？ HLA-DR？ Myeloid-Derived Suppressor Cells Impair Antimicrobial Responses in Patients with Acute-on-Chronic Liver Failure. Gut, 67, 1155-1167. https://doi.org/10.1136/gutjnl-2017-314184 |
| [33] | Bernsmeier, C., Pop, O.T., Singanayagam, A., et al. (2015) Patients with Acute-on-Chronic Liver Failure Have Increased Numbers of Regulatory Immune Cells Expressing the Receptor Tyrosine Kinase MERTK. Gastroenterology, 148, 603-615. https://doi.org/10.1053/j.gastro.2014.11.045 |
| [34] | Wen, Y., Lambrecht, J., Ju, C., et al. (2021) Hepatic Macrophages in Liver Homeostasis and Diseases-Diversity, Plasticity and Therapeutic Opportunities. Cellular & Molecular Immunology, 18, 45-56. https://doi.org/10.1038/s41423-020-00558-8 |
| [35] | Ogle, M.E., Segar, C.E., Sridhar, S., et al. (2016) Monocytes and Macrophages in Tissue Repair: Implications for Immunoregenerative Biomaterial Design. Experimental Biology and Medicine, 241, 1084-1097. https://doi.org/10.1177/1535370216650293 |
| [36] | Gr？nb？k, H., R？dgaard-Hansen, S., Aagaard, N.K., et al. (2016) Macrophage Activation Markers Predict Mortality in Patients with Liver Cirrhosis without or with Acute-on-Chronic Liver Failure (ACLF). Journal of Hepatology, 64, 813-822. https://doi.org/10.1016/j.jhep.2015.11.021 |
| [37] | Maras, J.S., Maiwall, R., Harsha, H.C., et al. (2015) Dysregulated Iron Homeostasis Is Strongly Associated with Multiorgan Failure and Early Mortality in Acute-on-Chronic Liver Failure. Hepatology, 61, 1306-1320. https://doi.org/10.1002/hep.27636 |
| [38] | Metzemaekers, M., Gouwy, M. and Proost, P. (2020) Neutrophil Chemoattractant Receptors in Health and Disease: Double-Edged Swords. Cellular & Molecular Immunology, 17, 433-450. https://doi.org/10.1038/s41423-020-0412-0 |
| [39] | Khanam, A., Trehanpati, N., Riese, P., et al. (2017) Blockade of Neutrophil’s Chemokine Receptors CXCR1/2 Abrogate Liver Damage in Acute-on-Chronic Liver Failure. Frontiers in Immunology, 8, Article 464. https://doi.org/10.3389/fimmu.2017.00464 |
| [40] | Wieser, V., Adolph, T.E., Enrich, B., et al. (2017) Reversal of Murine Alcoholic Steatohepatitis by Pepducin-Based Functional Blockade of Interleukin-8 Receptors. Gut, 66, 930-938. https://doi.org/10.1136/gutjnl-2015-310344 |
| [41] | Langer, M.M., Sichelschmidt, S., Bauschen, A., et al. (2023) Pathological Neutrophil Migration Predicts Adverse Outcomes in Hospitalized Patients with Liver Cirrhosis. Liver International, 43, 896-905. https://doi.org/10.1111/liv.15486 |
| [42] | Garfia, C., García-Ruiz, I. and Solís-Herruzo, J.A. (2004) Deficient Phospholipase C Activity in Blood Polimorphonuclear Neutrophils from Patients with Liver Cirrhosis. Journal of Hepatology, 40, 749-756. https://doi.org/10.1016/j.jhep.2004.01.004 |
| [43] | Boussif, A., Rolas, L., Weiss, E., et al. (2016) Impaired Intracellular Signaling, Myeloperoxidase Release and Bactericidal Activity of Neutrophils from Patients with Alcoholic Cirrhosis. Journal of Hepatology, 64, 1041-1048. https://doi.org/10.1016/j.jhep.2015.12.005 |
| [44] | Sherman, M.H. (2018) Stellate Cells in Tissue Repair, Inflammation, and Cancer. Annual Review of Cell and Developmental Biology, 34, 333-355. https://doi.org/10.1146/annurev-cellbio-100617-062855 |
| [45] | Rastogi, A., Bihari, C., Maiwall, R., et al. (2012) Hepatic Stellate Cells Are Involved in the Pathogenesis of Acute-on-Chronic Liver Failure (ACLF). Virchows Archiv, 461, 393-398. https://doi.org/10.1007/s00428-012-1291-2 |
| [46] | Lopez-Sanchez, G.N., Dominguez-Perez, M., Uribe, M., et al. (2020) The Fibrogenic Process and the Unleashing of Acute-on-Chronic Liver Failure. Clinical and Molecular Hepatology, 26, 7-15. https://doi.org/10.3350/cmh.2019.0011 |
| [47] | Katoonizadeh, A., Laleman, W., Verslype, C., et al. (2010) Early Features of Acute-on-Chronic Alcoholic Liver Failure: A Prospective Cohort Study. Gut, 59, 1561-1569. https://doi.org/10.1136/gut.2009.189639 |
| [48] | Hotchkiss, R.S. and Nicholson, D.W. (2006) Apoptosis and Caspases Regulate Death and Inflammation in Sepsis. Nature Reviews Immunology, 6, 813-822. https://doi.org/10.1038/nri1943 |
| [49] | Tazi, K.A., Bièche, I., Paradis, V., et al. (2007) In vivo Altered Unfolded Protein Response and Apoptosis in Livers from Lipopolysaccharide-Challenged Cirrhotic Rats. Journal of Hepatology, 46, 1075-1088. https://doi.org/10.1016/j.jhep.2007.01.034 |
| [50] | Claria, J., Arroyo, V. and Moreau, R. (2023) Roles of Systemic Inflammatory and Metabolic Responses in the Pathophysiology of Acute-on-Chronic Liver Failure. JHEP Reports: Innovation in Hepatology, 5, Article 100807. https://doi.org/10.1016/j.jhepr.2023.100807 |
| [51] | Caraceni, P., Riggio, O., Angeli, P., et al. (2018) Long-Term Albumin Administration in Decompensated Cirrhosis (ANSWER): An Open-Label Randomised Trial. The Lancet, 391, 2417-2429. https://doi.org/10.1016/S0140-6736(18)30840-7 |
| [52] | Fernandez, J., Claria, J., Amoros, A., et al. (2019) Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients with Decompensated Cirrhosis. Gastroenterology, 157, 149-162. https://doi.org/10.1053/j.gastro.2019.03.021 |
| [53] | Bernardi, M., Angeli, P., Claria, J., et al. (2020) Albumin in Decompensated Cirrhosis: New Concepts and Perspectives. Gut, 69, 1127-1138. https://doi.org/10.1136/gutjnl-2019-318843 |
| [54] | Pande, G., Hatti, M., Rai, M.K., et al. (2022) Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute-on-Chronic Liver Failure: A Proof-of-Concept Study. Journal of Inflammation Research, 15, 5027-5039. https://doi.org/10.2147/JIR.S377494 |
| [55] | Sort, P., Navasa, M., Arroyo, V., et al. (1999) Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis. The New England Journal of Medicine, 341, 403-409. https://doi.org/10.1056/NEJM199908053410603 |
| [56] | Fernandez, J., Angeli, P., Trebicka, J., et al. (2020) Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis. Clinical Gastroenterology and Hepatology, 18, 963-973. |
| [57] | Banares, R., Ibanez-Samaniego, L., Torner, J.M., et al. (2019) Meta-Analysis of Individual Patient Data of Albumin Dialysis in Acute-on-Chronic Liver Failure: Focus on Treatment Intensity. Therapeutic Advances in Gastroenterology, 12, 1-12. https://doi.org/10.1177/1756284819879565 |
| [58] | Niewinski, G., Raszeja-Wyszomirska, J., Hrenczuk, M., et al. (2020) Intermittent High-Flux Albumin Dialysis with Continuous Venovenous Hemodialysis for Acute-on-Chronic Liver Failure and Acute Kidney Injury. Artificial Organs, 44, 91-99. https://doi.org/10.1111/aor.13532 |
| [59] | Xiang, X., Feng, D., Hwang, S., et al. (2020) Interleukin-22 Ameliorates Acute-on-Chronic Liver Failure by Reprogramming Impaired Regeneration Pathways in Mice. Journal of Hepatology, 72, 736-745. https://doi.org/10.1016/j.jhep.2019.11.013 |
| [60] | Hwang, S., Hicks, A., Hoo, C.Z., et al. (2023) Novel Treatment of Acute and Acute-on-Chronic Liver Failure: Interleukin-22. Liver International. https://doi.org/10.1111/liv.15619 |
| [61] | Engelmann, C., Sheikh, M., Sharma, S., et al. (2020) Toll-Like Receptor 4 Is a Therapeutic Target for Prevention and Treatment of Liver Failure. Journal of Hepatology, 73, 102-112. https://doi.org/10.1016/j.jhep.2020.01.011 |
| [62] | He, Y., Guo, X., Lan, T., et al. (2021) Human Umbilical Cord-Derived Mesenchymal Stem Cells Improve the Function of Liver in Rats with Acute-on-Chronic Liver Failure via Downregulating Notch and Stat1/Stat3 Signaling. Stem Cell Research & Therapy, 12, Article 396. https://doi.org/10.1186/s13287-021-02468-6 |
