Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis.
Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis.
复制标题
原发性硬化性胆管炎中的胆管细胞衰老与疾病严重程度和预后相关。
DOI：
10.1016/j.jhepr.2021.100286
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Guido M
中科院分区：
文献类型：
--
作者：
Cazzagon N;Sarcognato S;Floreani A;Corrà G;De Martin S;Guzzardo V;Russo FP;Guido M
原发性硬化性胆管炎（PSC）是一种罕见的胆管疾病，病因不明。本研究旨在探讨PSC患者胆管细胞中细胞衰老（CS）标志物的表达及其与临床病理特征和预后的关系。35例PSC患者至少进行了一次肝脏采样。收集肝脏取样时的临床实验室数据。终点是无肝移植的生存期（LT），到肝移植的时间，无肝移植或肝硬化失代偿的生存期。根据Nakanuma进行组织学分级和分期。对CS标记物p16INK4A （p16）和p21WAF1/Cip1 （p21）进行免疫组化染色，并根据天然胆管（NBD）和导管反应（DR）的阳性程度进行3级评分。结果：p16在NBD和DR中的表达与纤维化（p均≤0.001）和分期（p分别= 0.006和p <0.001）直接相关。此外，NBD患者p16与肝炎活动性（HA）呈正相关（p = 0.026），而DR患者p16与胆管损失（BDL） （p = 0.005）和化生肝细胞（MH）直接相关（p <0.01）。p21在NBD和DR中的表达与HA（分别为p = 0.004和p = 0.043）、纤维化（分别为p = 0.006和p <0.001）、分期（分别为p = 0.006和p = 0.001）、BDL（分别为p = 0.002和p = 0.03）、DR和MH（均为p≤0.004）直接相关。通过多变量分析，p16在DR中的表达与分期（p = 0.001）、纤维化（p = 0.001）和BDL （p = 0.011）独立相关。p21在NBD中的表达与HA （p = 0.012）、BDL （p = 0.04）、DR （p = 0.014）独立相关。最后，p21在DR中的表达与无LT生存期、到LT生存时间和无不良结局生存期独立相关（p = 0.001, p = 0.017和p = 0.001）。胆管细胞衰老可在PSC的所有阶段检测到，并与组织学和临床疾病严重程度相关，可能代表新的预后和治疗靶点。在这项研究中，我们发现，在终末期原发性硬化性胆管炎（PSC）患者的肝脏中，胆管细胞衰老（CS）是一个早期事件，并且在所有疾病阶段都可以检测到。此外，我们观察到CS与组织学和临床疾病严重程度以及患者预后相关。因此，我们认为CS可能是PSC的一种新的预后工具和潜在的治疗靶点。协议号0034435,08/06/2020。胆管细胞衰老先前在终末期PSC中被描述过。胆管细胞衰老存在于PSC的所有阶段，可能代表早期发病事件。胆管细胞衰老与PSC患者的组织学和临床严重程度有关。胆管细胞衰老与PSC患者的预后独立相关。
Primary sclerosing cholangitis (PSC) is a rare cholangiopathy of unknown aetiopathogenesis. The aim of this study was to evaluate cellular senescence (CS) marker expression in cholangiocytes of patients with PSC and their correlation with clinical–pathological features and prognosis. Thirty-five patients with PSC with at least 1 available liver sampling were included. Clinical laboratory data at the time of liver sampling were collected. The endpoints were survival without liver transplantation (LT), time to LT, and survival without LT or cirrhosis decompensation. Histological grading and staging were assessed according to Nakanuma. Immunohistochemical stains for CS markers, p16INK4A (p16) and p21WAF1/Cip1 (p21), were performed and scored by a 3-tier scale based on positivity extent in native bile duct (NBD) and ductular reaction (DR). Results: p16 expression in NBD and DR was directly correlated with fibrosis (p ≤0.001 for both) and stage (p = 0.006 and p <0.001, respectively). Moreover, p16 in NBD was positively correlated with hepatitis activity (HA) (p = 0.026), whereas p16 in DR was directly correlated with bile duct loss (BDL) (p = 0.005) and metaplastic hepatocytes (MH) (p <0.01). p21 expression in NBD and DR was directly correlated with HA (p = 0.004 and p = 0.043, respectively), fibrosis (p = 0.006 and p <0.001, respectively), stage (p = 0.006 and p = 0.001, respectively), BDL (p = 0.002 and p = 0.03, respectively), and DR and MH (p ≤0.004 for all). By multivariate analysis, p16 expression in DR was independently associated with stage (p = 0.001), fibrosis (p = 0.001), and BDL (p = 0.011). p21 expression in NBD was independently associated with HA (p = 0.012), BDL (p = 0.04), and DR (p = 0.014). Finally, p21 expression in DR was independently associated with LT-free survival, time to LT, and adverse outcome-free survival (p = 0.001, p = 0.017, and p = 0.001, respectively). Cholangiocyte senescence is detectable in all stages of PSC and is associated with histological and clinical disease severity, potentially representing a new prognostic and therapeutic target. In this study, we showed that cholangiocyte senescence (CS), previously demonstrated in liver of patients with end-stage primary sclerosing cholangitis (PSC), is an early event and is detectable in all disease stages. Moreover, we observed that CS is associated with histological and clinical disease severity and patients’ outcome. Thus, we suggest that CS may represent a new prognostic tool and a potential therapeutic target in PSC. Protocol number 0034435, 08/06/2020. Cholangiocyte senescence was previously described in end-stage PSC. Cholangiocyte senescence is present in all stages of PSC and may represent an early pathogenic event. Cholangiocyte senescence is associated with histological and clinical severity in patients with PSC. Cholangiocyte senescence is independently associated with patients’ outcome in PSC.
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影响因子：
16.6
作者：
Ferreira-Gonzalez S;Lu WY;Raven A;Dwyer B;Man TY;O'Duibhir E;Lewis PJS;Campana L;Kendall TJ;Bird TG;Tarrats N;Acosta JC;Boulter L;Forbes SJ
通讯作者：
Forbes SJ
影响因子：
13.5
作者：
Tabibian, James H.;O'Hara, Steven P.;LaRusso, Nicholas F.
通讯作者：
LaRusso, Nicholas F.
影响因子：
25.7
作者：
Bergquist, A;Ekbom, A;Broomé, U
通讯作者：
Broomé, U
影响因子：
3.7
作者：
Aravinthan A;Pietrosi G;Hoare M;Jupp J;Marshall A;Verrill C;Davies S;Bateman A;Sheron N;Allison M;Alexander GJ
通讯作者：
Alexander GJ
影响因子：
25.7
作者：
de Vries, Elisabeth M. G.;Verheij, Joanne;Ponsioen, Cyriel Y.
通讯作者：
Ponsioen, Cyriel Y.