Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice.
OBJECTIVE
Circulating platelet counts gradually decrease in parallel with progression of chronic liver disease. Thrombocytopenia is a common complication of advanced liver fibrosis and is thought to be a consequence of the destruction of circulating platelets that occurs during secondary portal hypertension or hypersplenism. It is not clear whether thrombocytopenia itself affects liver fibrosis.


METHODS
Thrombocytopenic mice were generated by disruption of Bcl-xL, which regulates platelet life span, specifically in thrombocytes. Liver fibrosis was examined in thrombocytopenic mice upon bile duct ligation. Effect of platelets on hepatic stellate cells (HSCs) was investigated in vitro.


RESULTS
Thrombocytopenic mice developed exacerbated liver fibrosis, with increased expression of type I collagen alpha1 and alpha2, during cholestasis. In vitro experiments revealed that, upon exposure to HSCs, platelets became activated, released hepatocyte growth factor (HGF), and then inhibited HSC expression of the type I collagen genes in a Met signal-dependent manner. In contrast to the wild-type mice, the thrombocytopenic mice did not accumulate hepatic platelets or phosphorylate Met in the liver following bile duct ligation. Administration of recombinant HGF to thrombocytopenic mice reduced liver fibrosis to the levels observed in wild-type mice and attenuated hepatic expression of the type I collagen genes.


CONCLUSIONS
Thrombocytopenia exacerbates liver fibrosis; platelets have a previously unrecognized, antifibrotic role in suppressing type I collagen expression via the HGF-Met signaling pathway.
Kodama
Takahiro
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takehara
Tetsuo
T
Hikita
Hayato
H
Shimizu
Satoshi
S
Li
Wei
W
Miyagi
Takuya
T
Hosui
Atsushi
A
Tatsumi
Tomohide
T
Ishida
Hisashi
H
Tadokoro
Seiji
S
Ido
Akio
A
Tsubouchi
Hirohito
H
Hayashi
Norio
N
D000818:Animals; D002779:Cholestasis / Q000150:complications*; D003094:Collagen / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation; D013921:Thrombocytopenia / Q000150:complications*; D051020:bcl-X Protein / Q000502:physiology
C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D003094:Collagen