title: Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation.
abstract: Prostaglandins have been evaluated for their ability to reduce IRI after liver transplantation; however, poor stability, side effects and the inability to show a significant difference in primary endpoint have limited their clinical application. Treprostinil, a prostacyclin (PGI(2) ) analog, has a higher potency and longer elimination half-life than other commercially available PGI(2)  analogs. We examined the efficacy of treprostinil to prevent IRI during OLT. OLT was performed in syngeneic Lewis rats after 18 h of cold preservation (4°C) in the UW solution. IRI significantly increased serum ALT and AST levels, neutrophil infiltration, hepatic necrosis and mRNA levels of proinflammatory cytokines post-OLT, while treatment with treprostinil decreased all the parameters. Cold storage of liver grafts significantly reduced ATP levels and treprostinil restored energy levels in liver grafts early postreperfusion. In addition, treprostinil preserved the sinusoidal endothelial cell lining and reduced platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow was significantly compromised in the placebo group, whereas treprostinil maintained blood-flow similar to normal levels. Treprostinil protected the liver graft against IRI during OLT. Treprostinil has the potential to serve as a therapeutic option to protect the liver graft against I/R injury in patients undergoing OLT.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ghonem
authors.forename: J
authors.initials: J
authors.lastname: Yoshida
authors.forename: D B
authors.initials: DB
authors.lastname: Stolz
authors.forename: A
authors.initials: A
authors.lastname: Humar
authors.forename: T E
authors.initials: TE
authors.lastname: Starzl
authors.forename: N
authors.initials: N
authors.lastname: Murase
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D050377:Cold Ischemia; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D008102:Liver Circulation / Q000187:drug effects; D016031:Liver Transplantation / Q000009:adverse effects / Q000502:physiology*; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D011464:Epoprostenol; C427248:treprostinil