Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to university of wisconsin solution on reperfusion injury in liver transplantation.
BACKGROUND
Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury in nonhepatic organs, such as the heart. However, the role of p38 MAPK activation in the liver is unclear. We examined the effects of FR167653, a novel p38 MAPK inhibitor, as an additive to University of Wisconsin (UW) solution in rat liver transplantation.


METHODS
Rat orthotopic liver transplantation was performed after 30 hr of cold storage using UW solution with or without FR167653. Ten-day survival rates, serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels, liver tissue blood flow, histological findings, and activities of p38 MAPK and p46/p54 c-Jun N-terminal kinase (JNK) in liver grafts were evaluated.


RESULTS
The addition of FR167653 significantly increased animal survival rates. FR167653 significantly suppressed serum ALT and LDH levels and improved liver tissue blood flow after transplantation. FR167653 also ameliorated histological damage to the liver graft. Neither p38 MAPK nor p46/p54 JNKs was activated during cold storage, whereas both were markedly activated within 30 min of reperfusion and remained activated until 60 min after reperfusion. FR167653 inhibited the activation of p38 MAPK both 30 and 60 min after reperfusion, but it did not affect the activation of p46/p54 JNKs.


CONCLUSIONS
The addition of FR167653 to UW solution improved liver graft viability and animal survival rates associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting the activation of p38 MAPK may attenuate ischemia/reperfusion injury in liver transplantation.
Yoshinari
D
D
Second Department of Surgery, Gunna University School of Medicine, Japan.
Takeyoshi
I
I
Kobayashi
M
M
Koyama
T
T
Iijima
K
K
Ohwada
S
S
Matsumoto
K
K
Morishita
Y
Y
D000241:Adenosine; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol; D000818:Animals; D015925:Cryopreservation; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D005978:Glutathione; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008102:Liver Circulation; D016031:Liver Transplantation; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019188:Organ Preservation Solutions; D020033:Protein Isoforms / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D011887:Raffinose; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; C104334:FR 167653; D007328:Insulin; D019188:Organ Preservation Solutions; D020033:Protein Isoforms; D011720:Pyrazoles; D011725:Pyridines; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose