Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease.
Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease.
复制标题
DOI：
10.1371/journal.pone.0072904
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alexander GJ
中科院分区：
文献类型：
--
作者：
Aravinthan A;Pietrosi G;Hoare M;Jupp J;Marshall A;Verrill C;Davies S;Bateman A;Sheron N;Allison M;Alexander GJ
酒精相关肝病（ALD）仍然是肝脏相关发病率和死亡率的主要原因。在日常临床实践中，年龄、纤维化分期、MELD评分和持续饮酒可预测预后。在以前的研究中，肝细胞核面积增加和肝细胞p21表达增加，这两个衰老标志物，与非酒精相关性脂肪肝的纤维化分期增加和预后不良有关，而肝细胞核面积增加与ALD肝硬化的肝功能障碍有关。因此，本研究探讨了肝细胞周期时相分布和肝细胞p21表达与ALD结局的关系。研究了两个队列的肝脏切片。第一组包括42名ALD全谱患者。第二组包括77例ALD肝硬化患者。免疫组织化学评估了细胞周期时相标志物和p21的肝细胞表达。再生肝脏（n=12）和“正常”肝脏切片（n=5）分别作为阳性和阴性对照。在第一个队列中，几乎没有细胞周期进展超过G1/S期，肝细胞p21表达增加（p<0.0001），这与纤维化分期（p=0.005）和不良肝脏相关结局（p=0.03）独立相关。在第二个队列中，肝细胞p21表达（p<0.001）和MELD评分（p=0.006）均与不良肝脏相关结局独立相关;与肝细胞p21表达（AUROC 0.74; p=0.0002）的相关性强于MELD评分（AUROC 0.59; p=0.13）。此外，肝细胞p21表达与肝星状细胞活化增加共定位。这些发现与ALD中G1/S期以外的细胞周期进展受损一致。在两个队列中，肝细胞p21表达增加与纤维化分期和不良肝脏相关结局之间的显著独立相关性表明肝细胞衰老在ALD中起重要作用。检测肝细胞p21表达是一种简单而廉价的方法，在本系列研究中，它是评估ALD长期预后的一个有用指标。
Alcohol-related liver disease (ALD) remains a leading cause of liver-related morbidity and mortality. Age, fibrosis stage, MELD score and continued alcohol consumption predict outcome in everyday clinical practice. In previous studies increased hepatocyte nuclear area and hepatocyte expression of p21, both markers of senescence, were associated with increased fibrosis stage and a poor outcome in non-alcohol-related fatty liver disease, while increased hepatocyte nuclear area was related to liver dysfunction in ALD cirrhosis. This study, therefore, investigated the pattern of hepatocyte cell cycle phase distribution and hepatocyte p21 expression in relation to outcome in ALD. Liver sections from two cohorts were studied. The first comprised 42 patients across the full spectrum of ALD. The second cohort comprised 77 patients with ALD cirrhosis. Immunohistochemistry assessed hepatocyte expression of cell cycle phase markers and p21. Regenerating liver (n=12) and “normal” liver sections (n=5) served as positive and negative controls, respectively. In the first cohort there was little cell cycle progression beyond G1/S phase and increased hepatocyte p21 expression (p<0.0001), which correlated independently with fibrosis stage (p=0.005) and an adverse liver-related outcome (p=0.03). In the second cohort, both hepatocyte p21 expression (p<0.001) and MELD score (p=0.006) were associated independently with an adverse liver-related outcome; this association was stronger with hepatocyte p21 expression (AUROC 0.74; p=0.0002) than with MELD score (AUROC 0.59; p=0.13). Further, hepatocyte p21 expression co-localised with increased hepatic stellate cell activation. The findings are consistent with impaired cell cycle progression beyond the G1/S phase in ALD. The striking independent associations between increased hepatocyte p21 expression and both fibrosis stage and an adverse liver-related outcome in both cohorts suggests hepatocyte senescence plays an important role in ALD. Measuring hepatocyte p21 expression is simple and cheap and in this series was a useful measure of long-term prognosis in ALD.
登录
查看更多内容
影响因子：
3.4
作者：
Ozen, Alaattin;Kocak, Zafer;Karagol, Hakan
通讯作者：
Karagol, Hakan
影响因子：
25.7
作者：
Aravinthan, Aloysious;Scarpini, Cinzia;Alexander, Graeme
通讯作者：
Alexander, Graeme
酒精性肝病：发病机制和新的治疗靶点。
影响因子：
29.4
作者：
Gao B;Bataller R
通讯作者：
Bataller R
影响因子：
13.5
作者：
Michalopoulos, George K
通讯作者：
Michalopoulos, George K
影响因子：
1.9
作者：
Bell, H;Jahnsen, J;Sandvik, L
通讯作者：
Sandvik, L