Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis
Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis
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DOI：
10.1016/j.jhep.2015.04.003
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发表时间：
2015-09-01
影响因子：
25.7
通讯作者：
Spahr, Laurent
中科院分区：
文献类型：
--
作者：
Lanthier, Nicolas;Rubbia-Brandt, Laura;Spahr, Laurent
背景与目的：作为疾病严重程度标志的肝祖细胞（LPC）扩增的作用以及巨噬细胞活化对人类肝脏再生的影响尚不清楚。我们的目的是表征酒精性肝炎（AH）的LPC和巨噬细胞区室，以及基因表达模式，以确定在这种情况下良好预后的预测因子。方法：对58例AH患者入院后早期基线肝活检进行巨噬细胞、增生性肝细胞、总LPC和增生性LPC以及全肝微阵列基因表达的免疫组化研究。禁欲型肝硬化患者作为对照。根据基线后三个月MELD评分的变化，将患者分为“改善者”或“非改善者”。结果：与对照组相比，AH患者巨噬细胞显著扩增，LPC侵袭，增殖性肝细胞和LPC数量增加。在AH患者中，总LPC扩增（总角化蛋白7（+）细胞）与肝病严重程度相关。改善组（n = 34）在基线时的特征是，尽管临床和生物学变量相似，但与非改善组（n = 24）相比，增生性肝细胞、增生性LPC(双角化蛋白7（+)Ki67（+）细胞）和肝巨噬细胞的数量更高。改良基因的上调与细胞周期有丝分裂有关，并与SPINK1的主要表达有关。结论：肝巨噬细胞扩增、增殖性肝细胞和LPC数量增加以及细胞增殖相关基因上调与有利的结果相关。这些新发现为AH开辟了新的治疗靶点。(C) 2015欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: The role of liver progenitor cell (LPC) expansion, known as a marker of disease severity, as well as the impact of macrophage activation on liver regeneration remains unclear in humans. We aimed to characterize the LPC and macrophage compartments in alcoholic hepatitis (AH), as well as gene expression patterns to identify predictors of a good prognosis in this setting.Methods: Immunohistochemical studies for macrophages, proliferative hepatocytes, total and proliferative LPC, as well as whole liver microarray gene expression were performed on baseline liver biopsies of 58 AH patients early after admission. Abstinent cirrhotic patients were used as controls. Patients were qualified as "improvers'' or "non-improvers'' based on the change in MELD score three months after baseline.Results: Compared to controls, AH patients demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC. In AH patients, total LPC expansion (total Keratin7(+) cells) was associated with liver disease severity. The group of improvers (n = 34) was characterized at baseline by a higher number of proliferating hepatocytes, proliferative LPC (double Keratin7(+)Ki67(+) cells) and liver macrophages as compared to non-improvers (n = 24), despite similar clinical and biological variables. Upregulated genes in improvers were associated with cell cycle mitosis together with a major expression of SPINK1.Conclusions: Higher liver macrophage expansion, increased proliferative hepatocyte but also LPC number, as well as an upregulation of cell proliferation-related genes are associated with a favourable outcome. These new findings open novel therapeutic targets in AH. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.