Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats

Satoko Shiotani, Mitsuo Shimada, Taketoshi Suehiro, Yuji Soejima, Tomoharu Yosizumi, Hiroaki Shimokawa, Yoshihiko Maehara

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Background. Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. Methods. In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. Results. Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-α, interleukin-1β) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without fasudil died within 3 days, whereas 40% of those receiving fasudil survived (P<0.001). Conclusions. The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.

Original languageEnglish
Pages (from-to)375-382
Number of pages8
JournalTransplantation
Volume78
Issue number3
DOIs
Publication statusPublished - Aug 15 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Transplantation

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