title: Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.
abstract: Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. 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. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury.
authors: Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara Kanagawa, 252-0374, Japan.
authors: Hirotoki
authors: H
authors: Ohkubo
authors: Yoshiya
authors: Y
authors: Ito
authors: Tsutomu
authors: T
authors: Minamino
authors: Toshiaki
authors: T
authors: Mishima
authors: Mitsuhiro
authors: M
authors: Hirata
authors: Kanako
authors: K
authors: Hosono
authors: Masabumi
authors: M
authors: Shibuya
authors: Takehiko
authors: T
authors: Yokomizo
authors: Takao
authors: T
authors: Shimizu
authors: Masahiko
authors: M
authors: Watanabe
authors: Masataka
authors: M
authors: Majima
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: BLT1; neutrophil; regeneration; sinusoid