肝線維嚢胞性疾患における肝線維化の分子機構

肝纤维囊肿病肝纤维化的分子机制

• 批准号: 17790230
• 负责人: 佐藤 保則
• 金额: $ 2.18万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17790230/
• 关键词: 人体病理学; 肝臓; 胆管細胞; 肝線維化; 分子生物学

PCKラットの拡張肝内胆管を構成する胆管細胞には、病理組織学的に2種類の異なる形質を有するものがあることを見出した.すなわち、PCKラットの肝組織切片を用いた免疫染色で、通常の胆管細胞と同様の上皮系形質を有するものに加えて、胆管上皮マーカー(cytokeratin19, CK19)の発現が低下し、代わって間葉系マーカー(vimentin, fibronectin)が陽性を示す胆管細胞があることを明らかにした.さらに、PCKラットの培養胆管上皮細胞をTGF-β1で刺激すると、間葉系マーカー(vimentin)と細胞外マトリックス(fibronectin、collagen)の発現が著明に亢進し、一方、胆管上皮マーカー(CK19)の発現は低下した.一方、E-cadherin、タイトジャンクション蛋白(zonula occludens-1)の発現や細胞形態に変化はなく、α-SMA(筋線維芽細胞マーカー)の発現誘導も認めなかった.以上の成績から、PCKラットの胆管細胞はTGF-β1により脱分化を起こし間葉系細胞の性質を獲得することで、肝線維化に関与している可能性を示した.この胆管上皮細胞の性質の変化は筋線維芽細胞への分化ではなく、いわゆるepithelial to mesenchymal transition(EMT)とは異なる現象と考えられた.さらに、ヒト先天性肝線維症、カロリ病の肝組織切片でTGF-β1の細胞内シグナル伝達分子であるリン酸化Smad2の免疫染色を行った結果、胆管細胞におけるリン酸化Smad2の発現は対照群と比較して有意に増加していた.この結果から、ヒト先天性肝線維症、カロリ病においても胆管細胞が肝線維化に関与している可能性が示唆された.

The structure of bile duct cells in the liver of PCK is different from that of pathological tissues. Immunostaining of liver tissue sections of PCK and PCK showed that normal bile duct cells and epithelial cells of the same type were increased, and the development of bile duct epithelium (cytokeratin19, CK19) was decreased, and the development of mesenchymal cells (vimentin, fibronectin) was positive for bile duct cells. In addition, the expression of TGF-β1 in cultured bile duct epithelial cells stimulated by PCK and vimentin and extracellular fibronectin and collagen was significantly increased, while the expression of CK19 in cultured bile duct epithelial cells decreased. The development of cell morphology and the induction of development of α-SMA(tendon fibroblast cell) were studied. The above results indicate the possibility of TGF-β1 dedifferentiation in cholangiocytes and the acquisition of mesenchymal cell properties. The characteristics of bile duct epithelial cells and their differentiation are studied. Immunostaining of TGF-β1 in liver tissue sections of congenital liver diseases and chronic diseases showed that the expression of TGF-β1 in bile duct cells was significantly increased compared with that in control group. These results indicate the possibility of congenital hepatic vascular disease, cholangitis, and cholangiocarcinoma.

项目成果

Significance of Enhanced Expression of Nitric Oxide Syntheses in Splenic Sinus Lining Cells in Altered Portal Hemodynamics of Idiopathic Portal Hypertension

• DOI: 10.1007/s10620-006-9146-9
• 发表时间: 2007-04
• 期刊: Digestive Diseases and Sciences
• 影响因子: 3.1
• 作者: Yasunori Sato;S. Sawada;K. Kozaka;K. Harada;M. Sasaki;O. Matsui;Y. Nakanuma

Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib

• DOI: 10.2353/ajpath.2006.051136
• 发表时间: 2006-10-01
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Sato, Yasunori;Harada, Kenichi;Nakanuma, Yasuni
• 通讯作者: Nakanuma, Yasuni

Diffuse expression of heparin sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis

肥大细胞较多的纤维间隔中硫酸肝素蛋白多糖和结缔组织生长因子的弥漫表达与先天性肝纤维化未消退相关

• 发表时间: 2005
• 期刊: Liver Int 25(4)
• 作者: Sato Y;Nakanuma Y et al.;Sato Y.et al.;Ozaki S. et al.
• 通讯作者: Ozaki S. et al.

Ciliated hepatic cyst without smooth muscle layer : a variant ciliated hepatic foregut cyst?

无平滑肌层的纤毛性肝囊肿：一种变异的纤毛性前肠囊肿？

• 发表时间: 2006
• 期刊: Pathol Int 56・6
• 作者: Sato Y;Nakanuma Y et al.
• 通讯作者: Nakanuma Y et al.

Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease

• DOI: 10.1016/s0002-9440(10)62231-6
• 发表时间: 2005-01-01
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Sato, Y;Harada, K;Nakanuma, Y
• 通讯作者: Nakanuma, Y