Elsevier

Surgery

Volume 131, Issue 3, March 2002, Pages 344-349
Surgery

Original Communications
P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver*,**

https://doi.org/10.1067/msy.2002.121097Get rights and content

Abstract

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-α (TNF-α), and interleukin-1β (IL-1β) 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-α, and IL-1β 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-α and IL-1β 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. (Surgery 2002;131:344-9.)

Section snippets

Animals

Adult male Sprague-Dawley rats weighing 280 to 340 g were used in this experiment. Animals were allowed free access to food and water in a constant temperature environment with a 14-hour to 10-hour light-dark cycle. All animals were maintained in accordance with the guidelines described in the “Guide for the Care and Use of Laboratory Animals” (National Institutes of Health publication 85-23, revised 1985). This study was performed with the approval of the Animal Care and Experimentation

Results

After 2 hours of reperfusion, serum levels of AST, ALT, LDH, and TNF-α in the FR-treated group were significantly lower than those in the control group. Serum levels of IL-1β in the FR-treated group were lower than those in the control group; however, there was no significant difference. Serum levels of TNF-α and IL-1β in the FR-treated group were not significantly different from those in the sham-operated and FR-only groups. Serum levels of AST, ALT, and LDH in the FR-only group were not

Discussion

TNF-α and IL-β derived from activated Kupffer's cells play an important role in the pathogenesis of hepatic ischemia-reperfusion injury. These cytokines are capable of up-regulating adhesion molecules and cause polymorphonuclear neutrophils to adhere to endothelial cells. This causes microcirculation disturbance, which is thought to be a major mechanism of ischemia-reperfusion injury, including the “no-flow phenomenon.”23

MAPK family members are activated by dual phosphorylation on tyrosine and

Conclusion

In this warm ischemic model, both p38 MAPK and JNK were phosphorylated during the reperfusion process after ischemia. FR decreased serum TNF-α and IL-1β levels, liver injury associated with the inhibition of p38 MAPK activation, and the noninhibited phosphorylation of JNK. These results suggest that inhibiting the activation of p38 MAPK may attenuate warm ischemia-reperfusion injury of the liver.

References (32)

  • A Clerk et al.

    The p38-MAPK inhibitor, SB203580, inhibits cardiac stress-activated protein kinase/c-Jun N-terminal kinases (SAPKs/JNKs)

    FEBS Lett

    (1998)
  • R Ben-Levy et al.

    Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2

    Curr Biol

    (1998)
  • J Raingeaud et al.

    Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine

    J Biol Chem

    (1995)
  • Z Xia et al.

    Opposing effects of ERK and JNK-p38 MAP kinase on apoptosis

    Science

    (1995)
  • Y Koibuchi et al.

    Effects of estrogen and tamoxifen on the MAP kinase cascade in experimental rat breast cancer

    Int J Oncol

    (1997)
  • JM Kyriakis et al.

    The stress-activated protein kinase subfamily of c-Jun kinases

    Nature

    (1994)
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    *

    This work was supported in part by a fund from Fujisawa Pharmaceutical Co Ltd, Osaka, Japan.

    **

    Reprint requests: Izumi Takeyoshi, Second Department of Surgery, Gunma University School of Medicine, 3-39-15, Showa Machi, Maebashi, Gunma 371-8511, Japan.

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