title: Liver graft exposure to carbon monoxide during cold storage protects sinusoidal endothelial cells and ameliorates reperfusion injury in rats.
abstract: Hepatic ischemia/reperfusion (I/R) injury significantly influences short-term and long-term outcomes after liver transplantation (LTx). The critical step initiating the injury is known to include sinusoidal endothelial cell (SEC) alteration during the cold preservation period. As carbon monoxide (CO) has potent cytoprotective functions on vascular endothelial cells, this study examined if CO treatment of excised liver grafts during cold storage could protect SECs and ameliorate hepatic I/R injury. Rat liver grafts were preserved in University of Wisconsin (UW) solution containing 5% CO (CO-UW solution) for 18 to 24 hours and were transplanted into syngeneic Lewis rats. After 18 hours of cold preservation, SEC damage was evident with propidium iodide (PI) nuclear staining on SECs, and the frequency of PI(+) SECs was significantly lower in grafts stored in CO-UW solution versus those stored in control UW solution. SEC protection with CO was associated with decreased intercellular cell adhesion molecule translocation and less matrix metalloproteinase release during cold preservation. After LTx with 18 hours of cold preservation, serum alanine aminotransferase levels and hepatic necrosis were significantly less in the CO-UW group than in the control UW group. With 24 hours of cold storage, 35% (7/20) survived with control UW solution, whereas the survival with CO-UW solution improved to 80% (8/10). These beneficial effects of CO-UW solution were associated with a significant reduction of neutrophil extravasation, down-regulation of hepatic messenger RNA for tumor necrosis factor alpha and intercellular cell adhesion molecule 1, and less hepatic extracellular signal-regulated kinase activation. Liver grafts from Kupffer cell-depleted donors or pseudogerm-free donors showed less SEC death during cold preservation, and CO-UW solution further reduced SEC death. In conclusion, CO delivery to excised liver grafts during cold preservation efficiently ameliorates SEC damage and hepatic I/R injury.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ikeda
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueki
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Koji
authors.initials: K
authors.lastname: Tomiyama
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ross
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D015925:Cryopreservation / Q000379:methods*; D003451:Cryoprotective Agents / Q000494:pharmacology; D042783:Endothelial Cells / Q000473:pathology; D005978:Glutathione / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D006505:Hepatitis / Q000473:pathology / Q000517:prevention & control; D007328:Insulin / Q000494:pharmacology; D007728:Kupffer Cells / Q000473:pathology; D016031:Liver Transplantation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D055031:Primary Graft Dysfunction / Q000473:pathology / Q000517:prevention & control*; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D003451:Cryoprotective Agents; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D002248:Carbon Monoxide; D020782:Matrix Metalloproteinases; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose