Thrombocytopenia Exacerbates Cholestasis-Induced Liver Fibrosis in Mice

被引：147

作者：

Kodama, Takahiro ^{[1
]}

Takehara, Tetsuo ^{[1
]}

Hikita, Hayato ^{[1
]}

Shimizu, Satoshi ^{[1
]}

Li, Wei ^{[1
]}

Miyagi, Takuya ^{[1
]}

Hosui, Atsushi ^{[1
]}

Tatsumi, Tomohide ^{[1
]}

Ishida, Hisashi ^{[1
]}

Tadokoro, Seiji ^{[2
]}

Ido, Akio ^{[3
]}

Tsubouchi, Hirohito ^{[3
]}

Hayashi, Norio ^{[1
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Suita, Osaka 5650871, Japan

[2] Osaka Univ, Grad Sch Med, Dept Hematol & Oncol, Suita, Osaka 5650871, Japan

[3] Kagoshima Univ, Grad Sch Med & Dent Sci, Kagoshima 890, Japan

来源：

GASTROENTEROLOGY | 2010年 / 138卷 / 07期

关键词：

Bcl-2; Apoptosis; Cre; Conditional Knockout; HEPATOCYTE GROWTH-FACTOR; BILE-DUCT LIGATION; MOLECULAR-CLONING; PLATELETS; PROGRESSION; HEPATITIS; CIRRHOSIS; PLASMA; DAMAGE; DEATH;

D O I：

10.1053/j.gastro.2010.02.054

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

BACKGROUND & AIMS: 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 alpha 1 and alpha 2, 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.

引用

页码：2487 / U370

页数：19

共 34 条

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