Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
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不同的炎性体激活倾向于人类和实验性肝硬化的慢加急性肝衰竭，有或没有以前的失代偿。
DOI：
10.1136/gutjnl-2019-320170
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发表时间：
2021-03
期刊：
影响因子：
24.5
通讯作者：
Trebicka J
中科院分区：
文献类型：
--
作者：
Monteiro S;Grandt J;Uschner FE;Kimer N;Madsen JL;Schierwagen R;Klein S;Welsch C;Schäfer L;Jansen C;Claria J;Alcaraz-Quiles J;Arroyo V;Moreau R;Fernandez J;Bendtsen F;Mehta G;Gluud LL;Møller S;Praktiknjo M;Trebicka J
全身性炎症使急性失代偿（AD）肝硬化易于发展为慢加急性肝功能衰竭（ACLF）。支持性治疗可以改善AD患者，使其重新获得补偿。关于AD后再代偿患者的结局知之甚少。我们假设不同的炎性小体激活参与了代偿和再代偿患者的ACLF发展。前瞻性随访了249例肝硬化患者（分为代偿期和再代偿期（既往AD））的致死性ACLF发生情况。纳入了两个外部队列（n=327）（再代偿、AD和ACLF）。测量炎症体驱动白细胞介素（IL）、IL-1α（caspase-4/11依赖性）和IL-1β（caspase-1依赖性）。在大鼠中，胆管结扎诱导的肝硬化和脂多糖暴露用于诱导AD和随后的再补偿。测定IL-1α和IL-1β水平以及上游/下游基因表达。发生ACLF的患者显示出更高的IL基线水平。代偿期患者和可检测到IL的患者发生ACLF的比率高于代偿期患者。基线CLIF-C（欧洲慢性肝功能衰竭联盟研究基金会）AD、白蛋白和IL-1α是代偿患者发生ACLF的独立预测因子，CLIF-C AD和IL-1β是再代偿患者发生ACLF的独立预测因子。代偿组大鼠IL-1α基因表达升高，再代偿组大鼠IL-1β水平升高，肝脏基因表达升高。在两个外部队列中证实了发生ACLF的再代偿患者中IL-1β检测率较高，ACLF患者中IL-1α和IL-1β检测率较高。既往AD是致命性ACLF发展的重要风险因素，可能与炎性小体激活有关。动物模型证实了ACLF发展与代偿性肝硬化中的IL-1α和再代偿性肝硬化中的IL-1β之间的联系。
Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts. Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.
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影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
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影响因子：
82.9
作者：
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DOI：
10.1073/pnas.0709684105
发表时间：
2008-06-10
影响因子：
11.1
作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.82.4.1204
发表时间：
1985-01-01
影响因子：
11.1
作者：
KURTJONES, EA;BELLER, DI;UNANUE, ER
通讯作者：
UNANUE, ER