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Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: Increased expression of p21<sup>WAF1/Cip1</sup>as a disease marker and the influence of immunosuppressive drugs

Lunz, JG and Contrucci, S and Ruppert, K and Murase, N and Fung, JJ and Starzl, TE and Demetris, AJ (2001) Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: Increased expression of p21<sup>WAF1/Cip1</sup>as a disease marker and the influence of immunosuppressive drugs. American Journal of Pathology, 158 (4). 1379 - 1390. ISSN 0002-9440

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Abstract

Early chronic liver allograft rejection (CR) is characterized by distinctive cytological changes in biliary epithelial cells (BECs) that resemble cellular senescence, in vitro, and precede bile duct loss. If patients suffering from early CR are treated aggressively, the clinical and histopathological manifestations of CR can be completely reversed and bile duct loss can be prevented. We first tested whether the senescence-related p21WAF1/Cip1protein is increased in BECs during early CR, and whether treatment reversed the expression. The percentage of p21+ BECs and the number of p21+ BECs per portal tract is significantly increased in early CR (26 ± 17% and 3.6 ± 3.1) compared to BECs in normal liver allograft biopsies or those with nonspecific changes (1 ± 1% and 0.1 ± 0.3; P < 0.0001 and P < 0.02), chronic hepatitis C (2 ± 3% and 0.7 ± 1; P < 0.0001 and P < 0.04) or obstructive cholangiopathy (7 ± 7% and 0.7 ± 0.6; P < 0.006 and P = 0.04). Successful treatment of early CR is associated with a decrease in the percentage of p21+ BECs and the number of p21+ BECs per portal tract. In vitro, nuclear p21WAF1/Cip1expression is increased in large and multinucleated BECs, and is induced by transforming growth factor (TGF)-β. TGF-β1 also increases expression of TGF-β receptor II, causes phosphorylation of SMAD-2 and nuclear translocation of p21WAF1/Cip1, which inhibits BEC growth. Because conversion from cyclosporine to tacrolimus is an effective treatment for early CR, we next tested whether these two immunosuppressive drugs directly influenced BEC growth in vitro. The results show that cyclosporine, but not tacrolimus, stimulates BEC TGF-β1 production, which in turn, causes BEC mito-inhibition and up-regulation of nuclear p21WAF1/Cip1. In conclusion, expression of the senescence-related p21WAF1/Cip1protein is increased in BECs during early CR and decreases with successful recovery. Replicative senescence accounts for the characteristic BEC cytological alterations used for the diagnosis of early CR and lack of a proliferative response to injury. The ability of cyclosporine to inhibit the growth of damaged BECs likely accounts for the relative duct sparing properties of tacrolimus. © 2001 American Society for Investigative Pathology.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lunz, JG
Contrucci, S
Ruppert, Kruppertk@pitt.eduRUPPERTK
Murase, N
Fung, JJ
Starzl, TEtes11@pitt.eduTES11
Demetris, AJ
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 2001
Date Type: Publication
Journal or Publication Title: American Journal of Pathology
Volume: 158
Number: 4
Page Range: 1379 - 1390
DOI or Unique Handle: 10.1016/s0002-9440(10)64089-8
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0002-9440
Other ID: uls-drl:31735062120856, Starzl CV No. 2179
Date Deposited: 08 Apr 2010 17:37
Last Modified: 23 Jun 2018 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/5565

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