Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation
Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation
复制标题
DOI：
10.1007/s00795-022-00314-z
复制
发表时间：
2022-03
影响因子：
1.8
通讯作者：
Yudai Nakajima;Yuto Yamazaki;Xin Gao;Masatoshi Hashimoto;M. Nio;M. Wada;F. Fujishima;H. Sasano
中科院分区：
文献类型：
--
作者：
Yudai Nakajima;Yuto Yamazaki;Xin Gao;Masatoshi Hashimoto;M. Nio;M. Wada;F. Fujishima;H. Sasano
胆道闭锁（BA）是一种伴有肝外胆管阻塞的胆汁淤积性疾病，需要早期手术干预，偶尔需要肝移植（LT）。有毒胆汁酸的积累引起氧化应激，导致细胞损伤，如细胞衰老、线粒体功能障碍等。然而，它们的相互关联和临床意义的细节尚未被探索。因此，我们对接受Kasai门肠造口术（KP）和LT的BA患者的细胞衰老（p16和p21）、核双链DNA损伤（γH2AX）、自噬（p62）和mtDNA损伤（mtDNA拷贝数）标记物进行了免疫定位。我们研究了54例BA患者的肝活检标本，14例接受LT， 11例来自尸检的新生儿和婴儿肝脏。在肝细胞中，p21的表达在KP中显著升高。在胆管细胞中，p16在LT中表达显著升高，p21在KP中表达显著升高。p62在KP肝细胞和LT胆管细胞中的表达显著升高。此外，与对照组相比，KP和LT组mtDNA拷贝数显著减少。细胞衰老和线粒体DNA损伤进展依赖于BA的临床分期，可能作为LT的适应症标志。
Biliary atresia (BA) is a cholestatic disease with extrahepatic bile duct obstruction that requires early surgical intervention and occasionally liver transplantation (LT). Accumulation of toxic bile acids induces oxidative stress that results in cell damage, such as cell senescence, mitochondrial dysfunction and others. However, details of their reciprocal association and clinical significance are unexplored. Therefore, we used immuno-localization of markers for cell senescence (p16 and p21), nuclear double-strand DNA damage (γH2AX), autophagy (p62), and mtDNA damage (mtDNA copy number) in patients with BA who underwent Kasai portoenterostomy (KP) and LT. We studied liver biopsy specimens from 54 patients with BA, 14 who underwent LT and 11 from the livers of neonates and infants obtained at autopsy. In hepatocytes, p21 expression was significantly increased in KP. In cholangiocytes, p16 expression was significantly increased in LT, and p21 expression was significantly increased in KP. p62 expression was significantly increased in the KP hepatocytes and LT cholangiocytes. Furthermore, mtDNA copy number significantly decreased in KP and LT compared with the control. Cell senescence and mitochondrial DNA damage progression were dependent on the BA clinical stages and could possibly serve as the markers of indication of LT.