Almazroo, Omar
(2017)
PRECLINICAL AND CLINICAL EVALUATION OF TREPROSTINIL IN MINIMIZING HEPATIC ISCHEMIA AND REPERFUSION INJURY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Liver is a vital organ in the human body with important exocrine, endocrine and metabolic functions. Many clinical conditions such as viral infections as well as certain toxic substances can lead to liver damage, resulting in end-stage liver diseases. Orthotopic liver transplantation (OLT) is the only treatment option for various end-stage liver diseases. During the process of harvesting and preservation, the liver grafts are subjected to injury due to cold ischemia, and during transplantation, the liver graft is further injured by warm reperfusion of the blood. These events are referred to as Ischemia/Reperfusion (I/R) injury. I/R injury is a major leading cause of primary graft nonfunction (PNF) that can occur in 4 - 23% of OLTs, resulting in urgent re-transplantation. The I/R injury is an antigen independent component of liver harvesting process, which is associated with vasoconstriction, upregulation of cytokines, platelet aggregation, increase in reactive oxygen species and neutrophils infiltration. One promising approach to minimize I/R injury is to use pharmacological agents to prevent the impact of cold ischemia and warm reperfusion. Our hypothesis is that treprostinil, a prostacyclin I2 (PGI2) analog, due to its vasodilatory property, anti-platelet activity and inhibition of the release proinflammatory cytokines will attenuate the I/R injury of the liver. Treprostinil diminished the hepatic injury, minimized the associated effect of I/R injury on hepatic drug transporters gene expressions and maintained activity of Abcb1 (Mdr1; P-gp) and Cyp3a in an animal model where the livers were preserved in treprostinil supplemented UW solution and then perfused in an ex-vivo isolated perfused liver system. Incorporating treprostinil into the preservation solution may provide improved graft function. Clinically, liver transplant recipients tolerated continuous infusion of treprostinil for up to 5 days with an improved hepatic extraction of ICG, minimized need for ventilation support and hospitalizations without occurrence of any PNF. Given that treprostinil can be administered to liver transplanted patients safely, future studies should evaluate its efficacy in minimizing I/R injury of the livers. Improved preservation of the liver and decreasing I/R injury will be not only improving overall function of the livers transplanted, but will also increase the number of livers that can be transplanted.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
25 April 2017 |
| Date Type: |
Publication |
| Defense Date: |
22 November 2016 |
| Approval Date: |
25 April 2017 |
| Submission Date: |
11 April 2017 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
213 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Treprostinil; Ischemia and reperfusion injury; Liver transplantation; Isolated perfused rat liver; Clinical study |
| Date Deposited: |
25 Apr 2017 17:37 |
| Last Modified: |
25 Apr 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30894 |
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