Adhesion of platelets through thromboxane A₂ receptor signaling facilitates liver repair during acute chemical-induced hepatotoxicity.
OBJECTIVE
Platelets have been suggested to play an important role in liver regeneration and repair after hepatic resection and acute liver injury. However, the underlying mechanisms of liver repair remain elusive. Signaling through thromboxane prostanoid (TP) receptor participates in inflammation and tissue injury through platelet aggregation. On the other hand, TP receptor signaling also is involved in tissue repair and tumor growth through angiogenesis. The present study was examined whether or not TP receptor signaling contributes to liver repair and sinusoidal restoration from acute liver injury through platelet adhesion to the hepatic sinusoids.


METHODS
Carbon tetrachrolide (CCl4) was used to induce acute liver injury in TP receptor knockout mice (TP(-/-) mice) and their wild-type littermates (WT mice).


RESULTS
Compared with WT mice, TP(-/-) mice exhibited delayed in liver repair and sinusoidal restoration after CCl4 treatment, which were associated with attenuated hepatic expression of pro-angiogenic factors. Intravital microscopic observation revealed that adhering platelets to the sinusoids was increased in WT livers during the repair phase as compared with TP(-/-) livers, and platelet adhesion was dependent on TP receptor signaling. The levels of hepatocyte growth factor (HGF) in platelets from WT mice treated with CCl4 for 48h were greater than those form TP(-/-) mice, and HGF enhanced the expression of angiogenic factors in cultured human umbilical vein endothelial cells (HUVECs).


CONCLUSIONS
These results suggested that TP receptor signaling facilitates liver repair and sinusoidal restoration from acute liver injury through HGF release from platelets adhering to the sinusoids.
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Tsutomu
T
Minamino
Department of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Yoshiya
Y
Ito
Department of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Hirotoki
H
Ohkubo
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Yuki
Y
Shimuzu
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Ken
K
Kojo
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan; Department of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Nobuyuki
N
Nishizwa
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Hideki
H
Amano
Innovation Center for Immunoregulation Technologies and Drugs (AK project), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Shuh
S
Narumiya
Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Wasaburo
W
Koizumi
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan. Electronic address: mmajima@med.kitasato-u.ac.jp.
Masataka
M
Majima
D000704:Analysis of Variance; D000818:Animals; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000503:physiopathology*; D017931:DNA Primers / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D017931:DNA Primers; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride
Liver; Microcirculation; Platelet; Repair; Thromboxane