Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis.
BACKGROUND
Hepatic ischemia-reperfusion injury (I/R) occurs in the settings of transplantation, trauma, and elective liver resections. Reactive oxygen species (ROS) have been shown to play a major role in organ I/R injury. Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. The purpose of this study was to test the hypothesis that ethyl pyruvate (EP), a soluble pyruvate derivative, is effective in preventing hepatic I/R injury.


METHODS
Lewis rats underwent 60 minutes of partial warm hepatic ischemia. Three doses of EP dissolved in lactated Ringer's solution or lactated Ringer's solution (LR) alone were given by intravenous injection. Serum and tissue samples were obtained at 1 to 24 hours postreperfusion.


RESULTS
Serum transaminases, degree of hepatic necrosis, and neutrophil infiltration were all significantly decreased in the EP-treated rats compared with control animals. The amount of hepatic lipid peroxidation was also significantly decreased in EP-treated animals. Both circulating levels and hepatic expression of inflammatory cytokines were significantly decreased in the EP-treated animals. Furthermore, EP inhibited activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases, as well as nuclear factor-kappaB, signaling pathways involved in cytokine release. Treatment with EP also inhibited hepatic apoptosis.


CONCLUSIONS
EP has a protective effect on hepatic I/R injury, mediated in part by decreasing lipid peroxidation, down-regulation of inflammatory mediators, and inhibition of apoptosis. Strategies using this additive to LR solution should be considered in clinical settings of ischemic liver injury to decrease organ damage.
Tsung
Allan
A
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Kaizu
Takashi
T
Nakao
Atsunori
A
Shao
Lifang
L
Bucher
Brian
B
Fink
Mitchell P
MP
Murase
Noriko
N
Geller
David A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016207:Cytokines / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation; D008111:Liver Function Tests; D008297:Male; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011773:Pyruvates / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*
D016207:Cytokines; D011773:Pyruvates; C046522:ethyl pyruvate