Role of leukotriene B4 receptor 1 (BLT1) signaling in liver repair after hepatic ischemia reperfusion injury

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  • Ohkubo Hirotoki
    Departments of Pharmacology, Kitasato University School of Medicine Departments of Surgery, Kitasato University School of Medicine
  • Ito Yoshiya
    Departments of Surgery, Kitasato University School of Medicine
  • Kojo Ken
    Departments of Pharmacology, Kitasato University School of Medicine
  • Watanabe Masahiko
    Departments of Surgery, Kitasato University School of Medicine
  • Majima Masataka
    Departments of Pharmacology, Kitasato University School of Medicine

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Aims: Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages, and recruited macrophages play a critical role in liver repair and recovery from acute liver injury. The objective of the present study was to examine the role of LTB4 receptor 1 (BLT1) signaling in liver repair after hepatic ischemia/reperfusion (I/R) injury.<br><br>Methods: BLT1knockout mice (BLT1-/-) and wild-type mice (WT) were subjected to 60 min of partial (70%) hepatic warm ischemia followed by reperfusion. The process of liver repair after hepatic I/R was determined.<br><br>Results: In WT, ALT levels peaked at 6h, and then declined to controls at 96h. In BLT1-/-, ALT levels also peaked at 6h, but those at 48 and 96h (recovery phase) were 2-fold higher than WT. The necrotic area in WT peaked at 24h, and reduced gradually, while that in BLT1-/- was remained high until 96h. In BLT1-/-, the expression of proliferating cell nuclear antigen (PCNA) was delayed, which was associated with reduced levels of hepatic mRNA expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Recruitment of VEGFR1-positive macrophages expressing EGF in injured liver from BLT1-/- was attenuated. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro.<br><br>Conclusions: BLT1 signaling plays an important role in liver repair after hepatic I/R through enhanced EGF expression in recruited macrophages.

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