Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF
Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF
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DOI：
10.1016/j.jhep.2022.07.006
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发表时间：
2022-10-14
影响因子：
25.7
通讯作者：
Jalan, Rajiv
中科院分区：
文献类型：
--
作者：
Engelmann, Cornelius;Habtesion, Abeba;Jalan, Rajiv
背景和目标：慢性加急性肝衰竭（ACLF）的特征是短期死亡率高，全身炎症和肝再生失败。它的治疗是一个主要的未满足的医疗需求。本研究旨在探讨联合TAK-242（一种Toll样受体-4（TLR 4）拮抗剂）与粒细胞集落刺激因子（G-CSF）是否可以减轻炎症，同时增强肝再生。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）作为肝外或肝损伤。每天给予G-CSF和/或TAK-242。结果：在LPS诱导的ACLF的小鼠模型中，用G-CSF治疗与显著的死亡率相关（48小时后66%对没有G-CSF的0%）。在G-CSF中添加TAK-242可消除死亡率（0%），并显著降低肝细胞死亡、巨噬细胞浸润和炎症。在GalN模型中，G-CSF和TAK-242单独使用时均能减轻肝损伤，但联合使用的有效性显著更高。G-CSF治疗（联合或不联合TAK-242）与促再生和抗凋亡STAT 3通路的激活相关。LPS驱动的ACLF的特征在于p21过表达，这表明肝衰老和肝细胞再生的抑制。虽然TAK-242治疗减轻了对衰老的影响，但当与TAK-242联合给药时，G-CSF导致肝细胞再生标志物显著增加。结论：TAK-242和G-CSF联合给药可抑制炎症，促进肝再生并预防ACLF模型的死亡;因此，该联合给药可能是ACLF的潜在治疗选择。慢加急性肝衰竭与严重的肝脏炎症和短期生存率低有关。因此，迫切需要有效的治疗方法。在本文中，我们使用小鼠模型表明，粒细胞集落刺激因子（可促进肝再生）和TAK-242（可抑制在炎症中起关键作用的受体）联合治疗可有效治疗慢性加急性肝衰竭。(c)2022作者由Elsevier B. V.代表欧洲肝脏研究协会出版。这是CC BY许可下的开放获取文章（http：creativecommons.org/licenses/by/4）。0/）。
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.Methods: 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.Results: 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.Conclusion: 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.Lay summary: 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. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4. 0/).