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Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.

ABSTRACT: Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important phenotype in PSC. We assessed markers of cellular senescence and senescence-associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We tested whether endogenous and exogenous biliary constituents affect senescence and SASP in cultured human cholangiocytes. We determined in coculture whether senescent cholangiocytes induce senescence in bystander cholangiocytes. Finally, we explored signaling mechanisms involved in cholangiocyte senescence and SASP. In vivo, PSC cholangiocytes expressed significantly more senescence-associated p16(INK4a) and ?H2A.x compared to the other three conditions; expression of profibroinflammatory SASP components (i.e., IL-6, IL-8, CCL2, PAI-1) was also highest in PSC cholangiocytes. In vitro, several biologically relevant endogenous (e.g., cholestane 3,5,6 oxysterol) and exogenous (e.g., lipopolysaccharide) molecules normally present in bile induced cholangiocyte senescence and SASP. Furthermore, experimentally induced senescent human cholangiocytes caused senescence in bystander cholangiocytes. N-Ras, a known inducer of senescence, was increased in PSC cholangiocytes and in experimentally induced senescent cultured cholangiocytes; inhibition of Ras abrogated experimentally induced senescence and SASP.Cholangiocyte senescence induced by biliary constituents by way of N-Ras activation is an important pathogenic mechanism in PSC. Pharmacologic inhibition of N-Ras with a resultant reduction in cholangiocyte senescence and SASP is a new therapeutic approach for PSC.

SUBMITTER: Tabibian JH

PROVIDER: S-EPMC4167827 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.

Tabibian James H JH O'Hara Steven P SP Splinter Patrick L PL Trussoni Christy E CE LaRusso Nicholas F NF

Hepatology (Baltimore, Md.) 20140425 6

<h4>Unlabelled</h4>Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important phenotype in PSC. We assessed markers of cellular senescence and senescence-associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We ...[more]

PMID: 24390753

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Project description:Background & aimsPrimary 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.MethodsThirty-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).ConclusionsCholangiocyte 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.Lay summaryIn 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.Clinical trial numberProtocol number 0034435, 08/06/2020.

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Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.

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Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.

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