Engelmann Cornelius, Habtesion Abeba, Hassan Mohsin, Kerbert Annarein Jc, Hammerich Linda, Novelli Simone, Fidaleo Marco, Philips Alexandra, Davies Nathan, Ferreira-Gonzalez Sofia, Forbes Stuart J, Berg Thomas, Andreola Fausto, Jalan Rajiv
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany; Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany; Berlin Institute of Health - Charité - Universitätsmedizin Berlin, Germany.
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
J Hepatol. 2022 Nov;77(5):1325-1338. doi: 10.1016/j.jhep.2022.07.006. Epub 2022 Jul 16.
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic inflammation, and failure of hepatic regeneration. Its treatment is a major unmet medical need. This study was conducted to explore whether combining TAK-242, a Toll-like receptor-4 (TLR4) antagonist, with granulocyte-colony stimulating factor (G-CSF), could reduce inflammation whilst enhancing liver regeneration.
Two mouse models of ACLF were investigated. Chronic liver injury was induced by carbon tetrachloride; lipopolysaccharide (LPS) or galactosamine (GalN) were then administered as extrahepatic or hepatic insults, respectively. G-CSF and/or TAK-242 were administered daily. Treatment durations were 24 hours and 5 days in the LPS model and 48 hours in the GalN model.
In a mouse model of LPS-induced ACLF, treatment with G-CSF was associated with significant mortality (66% after 48 hours vs. 0% without G-CSF). Addition of TAK-242 to G-CSF abrogated mortality (0%) and significantly reduced liver cell death, macrophage infiltration and inflammation. In the GalN model, both G-CSF and TAK-242, when used individually, reduced liver injury but their combination was significantly more effective. G-CSF treatment, with or without TAK-242, was associated with activation of the pro-regenerative and anti-apoptotic STAT3 pathway. LPS-driven ACLF was characterised by p21 overexpression, which is indicative of hepatic senescence and inhibition of hepatocyte regeneration. While TAK-242 treatment mitigated the effect on senescence, G-CSF, when co-administered with TAK-242, resulted in a significant increase in markers of hepatocyte regeneration.
The combination of TAK-242 and G-CSF inhibits inflammation, promotes hepatic regeneration and prevents mortality in models of ACLF; thus, this combination could be a potential treatment option for ACLF.
Acute-on-chronic liver failure is associated with severe liver inflammation and poor short-term survival. Therefore, effective treatments are urgently needed. Herein, we have shown, using mouse models, that the combination of granulocyte-colony stimulating factor (which can promote liver regeneration) and TAK-242 (which inhibits a receptor that plays a key role in inflammation) could be effective for the treatment of acute-on-chronic liver failure.
慢加急性肝衰竭（ACLF）的特征为短期死亡率高、全身炎症反应以及肝再生功能衰竭。其治疗是一项尚未满足的重大医疗需求。本研究旨在探讨将Toll样受体4（TLR4）拮抗剂TAK-242与粒细胞集落刺激因子（G-CSF）联合使用，是否能在减轻炎症的同时增强肝再生。
研究了两种ACLF小鼠模型。通过四氯化碳诱导慢性肝损伤；然后分别给予脂多糖（LPS）或半乳糖胺（GalN）作为肝外或肝内损伤因素。每天给予G-CSF和/或TAK-242。在LPS模型中治疗持续时间为24小时和5天，在GalN模型中为48小时。
在LPS诱导的ACLF小鼠模型中，G-CSF治疗与显著的死亡率相关（48小时后为66%，而未使用G-CSF时为0%）。在G-CSF中添加TAK-242可消除死亡率（0%），并显著减少肝细胞死亡、巨噬细胞浸润和炎症。在GalN模型中，单独使用G-CSF和TAK-242均可减轻肝损伤，但二者联合使用效果显著更佳。无论是否使用TAK-242，G-CSF治疗均与促再生和抗凋亡的信号转导及转录激活因子3（STAT3）通路的激活相关。LPS驱动的ACLF的特征是p21过表达，这表明肝衰老和肝细胞再生受到抑制。虽然TAK-242治疗减轻了对衰老的影响，但G-CSF与TAK-242联合使用时，肝细胞再生标志物显著增加。
在ACLF模型中，TAK-242与G-CSF联合使用可抑制炎症、促进肝再生并预防死亡；因此，这种联合用药可能是ACLF的一种潜在治疗选择。
慢加急性肝衰竭与严重的肝脏炎症和短期生存率低相关。因此，迫切需要有效的治疗方法。在此，我们利用小鼠模型表明，粒细胞集落刺激因子（可促进肝再生）与TAK-242（可抑制在炎症中起关键作用的一种受体）联合使用可能对慢加急性肝衰竭的治疗有效。
