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PRECLINICAL AND CLINICAL EVALUATION OF TREPROSTINIL IN MINIMIZING HEPATIC ISCHEMIA AND REPERFUSION INJURY

Almazroo, Omar (2017) PRECLINICAL AND CLINICAL EVALUATION OF TREPROSTINIL IN MINIMIZING HEPATIC ISCHEMIA AND REPERFUSION INJURY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Almazroo, Omaroaa11@pitt.eduoaa110000-0002-9727-7051
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.eduRV
Committee MemberEmpey, Philip E.pempey@pitt.eduPEMPEY
Committee MemberBeumer, Jan H.jhb11@pitt.eduJHB11
Committee MemberMa, Xiaochaomxiaocha@pitt.eduMXIAOCHA
Committee MemberTevar, Amit D.adt35@pitt.eduADT35
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 2017 17:37
URI: http://d-scholarship.pitt.edu/id/eprint/30894

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