慢加急性肝衰竭研究的新视角:肝纤维化与损伤抵抗
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摘要
慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)是我国及亚太地区慢性肝病患者常见的危重急症,其发病机制尚未完全阐明,且目前缺乏有效的治疗方法.近年研究显示,与发生在无慢性肝病基础上的急性肝衰竭患者相比,有慢性肝病基础的患者抵抗后续急性打击的能力更强.该发现促使临床专家和基础研究者从慢性肝病基础上损伤抵抗这一新的角度出发来探讨ACLF的发病机制.本文就肝纤维化基础上损伤抵抗(模拟ACLF)现象及其细胞与分子机制的研究现状作一述评,以期为阐明ACLF的发病机制及寻找新的治疗靶点提供理论依据.
Acute-on-chronic liver failure(ACLF) is an increasingly recognized entity encompassing an acute deterioration of liver function in patients with pre-existing chronic liver diseases, which is usually associated with a precipitating event. Compared to acute liver failure, ACLF patients exhibit relatively slow disease progression and prolonged survival. Recent studies show that patients without previous decompensation have higher short-term mortality than those with prior hepatic decompensation. These interesting and important facts motivate clinicians and researchers to dissect the underlying mechanisms of ACLF from a new perspective, namely, the correlation between chronic liver diseases and injury resistance. In this review, we will make a comment on the phenomena as well as cellular and molecular mechanisms behind injury resistance in the setting of hepatic fibrosis(simulating the development of ACLF), in hopes of providing novel insights into the pathogenesis and therapy of ACLF.
Acute-on-chronic liver failure(ACLF) is an increasingly recognized entity encompassing an acute deterioration of liver function in patients with pre-existing chronic liver diseases, which is usually associated with a precipitating event. Compared to acute liver failure, ACLF patients exhibit relatively slow disease progression and prolonged survival. Recent studies show that patients without previous decompensation have higher short-term mortality than those with prior hepatic decompensation. These interesting and important facts motivate clinicians and researchers to dissect the underlying mechanisms of ACLF from a new perspective, namely, the correlation between chronic liver diseases and injury resistance. In this review, we will make a comment on the phenomena as well as cellular and molecular mechanisms behind injury resistance in the setting of hepatic fibrosis(simulating the development of ACLF), in hopes of providing novel insights into the pathogenesis and therapy of ACLF.
引文
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9 Bai L,Kong M,Zheng Q,Zhang X,Liu X,Zu K,Chen Y,Zheng S,Li J,Ren F,Lou J,Liu S,Duan Z.Inhibition of the translocation and extracellular release of high-mobility group box 1 alleviates liver damage in fibrotic mice in response to D-galactosamine/lipopolysaccharide challenge.Mol Med Rep 2016;13:3835-3841[PMID:27035642 DOI:10.3892/mmr.2016.5003]
10 Bai L,Zu K,Zhang X,Ren F,Zheng S,Chen Y,Duan Z.Protective effects and possible mechanisms of hepatic fibrosis against APAP-induced lethal injury.Zhonghua Gan Zang Bing Za Zhi 2015;23:161-165[PMID:25938825 DOI:10.3760/cma.j.issn.1007-3418.2015.03.001]
11 Bai L,Liu X,Zheng Q,Kong M,Zhang X,Hu R,Lou J,Ren F,Chen Y,Zheng S,Liu S,Han YP,Duan Z,Pandol SJ.M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes.Sci Rep 2017;7:10518[PMID:28874845 DOI:10.1038/s41598-017-11303-z]
12 Osawa Y,Hannun YA,Proia RL,Brenner DA.Roles of AKTand sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver.Hepatology 2005;42:1320-1328[PMID:16317686 DOI:10.1002/hep.20967]
13 Osawa Y,Seki E,Adachi M,Suetsugu A,Ito H,Moriwaki H,Seishima M,Nagaki M.Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice.Hepatology2010;51:237-245[PMID:19821528 DOI:10.1002/hep.23262]
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15 Chalasani N,Aljadhey H,Kesterson J,Murray MD,Hall SD.Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity.Gastroenterology 2004;126:1287-1292[PMID:15131789]
16 Watkins PB,Kaplowitz N,Slattery JT,Colonese CR,Colucci SV,Stewart PW,Harris SC.Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily:a randomized controlled trial.JAMA 2006;296:87-93[PMID:16820551 DOI:10.1001/jama.296.1.87]
17 Wynn TA,Vannella KM.Macrophages in Tissue Repair,Regeneration,and Fibrosis.Immunity 2016;44:450-462[PMID:26982353 DOI:10.1016/j.immuni.2016.02.015]
18 Tacke F.Targeting hepatic macrophages to treat liver diseases.J Hepatol 2017;66:1300-1312[PMID:28267621 DOI:10.1016/j.jhep.2017.02.026]
19 Ju C,Tacke F.Hepatic macrophages in homeostasis and liver diseases:from pathogenesis to novel therapeutic strategies.Cell Mol Immunol 2016;13:316-327[PMID:26908374 DOI:10.1038/cmi.2015.104]
20 Hamidzadeh K,Christensen SM,Dalby E,Chandrasekaran P,Mosser DM.Macrophages and the Recovery from Acute and Chronic Inflammation.Annu Rev Physiol 2017;79:567-592[PMID:27959619 DOI:10.1146/annurevphysiol-022516-034348]
21 Sica A,Invernizzi P,Mantovani A.Macrophage plasticity and polarization in liver homeostasis and pathology.Hepatology2014;59:2034-2042[PMID:24115204 DOI:10.1002/hep.26754]
22 Murray PJ.Macrophage Polarization.Annu Rev Physiol2017;79:541-566[PMID:27813830 DOI:10.1146/annurevphysiol-022516-034339]
23 Okabe Y,Medzhitov R.Tissue-specific signals control reversible program of localization and functional polarization of macrophages.Cell 2014;157:832-844[PMID:24792964 DOI:10.1016/j.cell.2014.04.016]
24 Sun YY,Li XF,Meng XM,Huang C,Zhang L,Li J.Macrophage Phenotype in Liver Injury and Repair.Scand JImmunol 2017;85:166-174[PMID:27491503 DOI:10.1111/sji.12468]
25 Tacke F,Zimmermann HW.Macrophage heterogeneity in liver injury and fibrosis.J Hepatol 2014;60:1090-1096[PMID:24412603 DOI:10.1016/j.jhep.2013.12.025]
26 Dalmas E,Clément K,Guerre-Millo M.Defining macrophage phenoty peand function inadiposetissue.Trends Immunol 2011;32:307-314[PMID:21616718 DOI:10.1016/j.it.2011.04.008]
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