Orthotopic liver transplantation (OLT) is the only curative therapy for end-stage liver diseases. To overcome organ shortage, organs from extended criteria donors, which would ordinarily be discarded, are used sometimes. These organs provide additional grafts; however, they are more susceptible to ischemia-reperfusion (I/R) injury. I/R injury, an unavoidable process during OLT, is a major cause of liver graft non-function and failure, requiring urgent re-transplantation, which further depletes the scare organ pool. To date, no therapy is available to reduce or prevent I/R injury.
Prostaglandins (PG) have well characterized vasodilatory and anti-platelet aggregatory actions. Many PG analogues, including prostacyclin (PGI2), have been evaluated for their ability to reduce hepatic I/R injury after OLT. Poor stability, intolerable side effects, and the inability to show a significant difference in primary endpoint have limited their clinical application so far. Treprostinil, a relatively new FDA-approved PGI2 analogue, has a higher stability, potency, and longer elimination half-life than other PGI2 analogues available.
The objectives of this dissertation were to examine the efficacy of treprostinil in protecting the liver graft against I/R injury during OLT. Proof of concept of treprostinil minimizing hepatic I/R injury was demonstrated in a rat OLT model. Further analysis showed that I/R injury significantly down-regulated CYP2E1, CYP2C11, and CYP3A mRNA, protein expression, and activity, as well as the expression of several hepatic transporters in liver graft post-OLT. Treprostinil improved hepatic expression and activity of CYP450 enzymes and transporters. In particular, Bsep mRNA expression was restored to normal and Mrp2 and P-gp protein expression were up-regulated. In vitro studies confirmed that treprostinil does not inhibit or induce the metabolism of immunosuppressive medications. These findings support co-administration of treprostinil with cyclosporine A, tacrolimus, sirolimus, or mycophenolic acid to adult OLT patients without concern for any drug-drug interaction.
This is the first study to examine the efficacy of treprostinil for protection of liver grafts against I/R injury during OLT. A clinical study has been initiated to examine the safety and efficacy of perioperative treprostinil administration to adult OLT patients. Collectively, this work makes significant contributions to the field of liver transplantation and, potentially, solid organ transplantation.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-01102011-103719 |
| Date | 11 January 2011 |
| Creators | Ghonem, Nisanne Sarah |
| Contributors | Wen Xie, MD, PhD, Noriko Murase, MD, Raman Venkataramanan, PhD, Donna B. Stolz, PhD, Stephen C. Strom, PhD, Michael Zemaitis, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-01102011-103719/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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