P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver.
BACKGROUND
Several studies have implicated the mitogen-activated protein kinase (MAPK) signal pathway in non-hepatic organ ischemia-reperfusion injury. However, the role of p38 MAPK in hepatic ischemia-reperfusion injury remains unclear. This study investigated the role of p38 MAPK in hepatic ischemia-reperfusion injury.


METHODS
Male Sprague-Dawley rats were divided into 4 groups (sham, FR-only, control, and FR-treated groups). The animals in the control and FR-treated groups were subjected to 30 minutes of warm ischemia with congestion of the gut. The FR-only and FR-treated groups received FR167653 (FR), which is a novel p38 MAPK inhibitor. The serum levels of aspartate transaminase, alanine transaminase, lactate dehydrogenase, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured (each, n = 6). Liver tissue blood flow was measured at pre-ischemia, end-ischemia, and 30, 60, 90, and 120 minutes after reperfusion (each, n = 4). The liver tissues in the control and FR-treated groups were excised for p38 MAPK and c-Jun N-terminal kinase (JNK) analyses and histopathology (each, n = 4).


RESULTS
Serum levels of aspartate transaminase, alanine transaminase, lactate dehydrogenase, TNF-alpha, and IL-1beta were significantly lower in the FR-treated group than in the control group, and liver tissue blood flow was significantly higher in the FR-treated group than in the control group. Histopathologically, tissue damage was milder in the FR-treated group than in the control group. Both p38 MAPK and JNK were markedly phosphorylated after 30 minutes of reperfusion, and FR inhibited the phosphorylation of p38 MAPK without affecting the JNK.


CONCLUSIONS
FR decreased serum TNF-alpha and IL-1beta levels and liver injury associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting the activation of p38 MAPK may attenuate warm ischemia-reperfusion injury of the liver.
Kobayashi
Mitsunobu
M
Second Department of Surgery, Gunma University School of Medicine, Department of Pathology, Nippon Medical School Second Hospital, Kawasaki, Japan.
Takeyoshi
Izumi
I
Yoshinari
Daisuke
D
Matsumoto
Koshi
K
Morishita
Yasuo
Y
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000097:blood; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; C104334:FR 167653; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases