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向, 宗徳
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[原著 / Originals] 平成24年1月18日受付, 平成24年3月15日受理.
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Juanjuan, Zhao ; Okamoto, Yasuo ; Takuwa, Yoh
概要:
The lysophospholipid mediator sphingosine-1-phosphate (S1P) exerts diverse biological activities including the regulatio
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n of leukocyte migration and vascular barrier integrity, suggesting that S1P signaling could be involved in inflammatory fibrotic diseases. Pulmonary fibrosis is a devastating disease characterized by fibroblast accumulation and extracellular matrix deposition in lungs, and bleomycin–induced pulmonary fibrosis is the most widely used experimental model. We studied the effects of the S1P–specific receptor S1P2 on the phenotypes of lung fibroblasts isolated from bleomycin- and saline-administered wild-type and S1P2–null (S1pr2-/-) mice. The lung fibroblasts from bleomycin-administered wild-type and S1pr2-/- mice failed to proliferate in the presence of serum, unlike fibroblasts from saline-administered mice. The fibroblasts from bleomycin-administered mice also showed the enlarged and flattened morphology compared with fibroblasts from control mice. Bleomycin administration increased the protein expression of the cell cycle inhibitor p16INK4a in fibroblasts and the number of senescence–associated β-galactosidase (SA-β-gal)-positive fibroblasts. In S1pr2-/- fibroblasts, bleomycin administration-induced increases in p16INK4a protein expression and SA–β-gal–positive cells were augmented. Furthermore, bleomycin increased mRNA expression of interleukin-6 and matrix metalloproteinases in S1pr2-/- fibroblasts compared with wild-type fibroblasts. In addition, the activation of Akt in response to platelet–derived growth factor and S1P was enhanced in S1pr2-/- fibroblasts compared with wild-type fibroblasts. These results indicate that S1P2 deletion enhances bleomycin administration–induced cellular senescence of lung fibroblasts, which may lead to inhibition of lung fibrosis through the mechanisms involving increased matrix metalloproteinases expression. Thus, S1P2 may be a novel therapeutic target for lung fibrosis.
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| 3.
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佐々木, 素子 ; 宮腰, 菜沙美 ; 佐藤, 保則 ; 中沼, 安二
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佐々木, 素子 ; 宮腰, 菜沙美 ; 佐藤, 保則 ; 中沼, 安二
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| 5.
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佐々木, 素子 ; Sasaki, Motoko
概要:
肝内胆管消失症候群における胆管再生・修復機構を解析する目的で、原発性胆汁性肝硬変(PBC)を含む肝内胆管消失症候群45例と対照疾患肝43例,正常肝22例の人体材料を用いて免疫組織化学的に、肝内胆管上皮における粘膜再生因子TFF1〜3とTFF
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2受容体候補分子DMBT1,肝細胞増殖因子(HGF)関連因子(HGFA,HAI-1,cMET)の発現と胆管細胞老化について検討した。肝内胆管系では胆管レベルと胆管障害に応じた特徴的なTFF1〜3,DMBT1発現がみちれ,大型胆管では主にTFF1,3/DMBT1が,小型胆管では主にTFF2/DMBT1が粘膜防御に働くことが示唆された。特にPBCでは胆管障害部を中心にTFF2とDMBT1発現の亢進が見られた。HGF関連分子では、PBCの胆管障害部に特徴的にHAI-1発現亢進が見られた。さらに組織化学的検討と細胞老化関連p21^<WAF1/Cip1>,p16^<INK4a>,p16^<INK4a>抑制因子Bmi1発現の検討から、移植後慢性拒絶肝の肝内胆管とPBCの肝内小型胆管障害部には高率にp21^<WAF1/Cip1>,p16^<INK4a>の発現亢進を伴う胆管細胞の老化がみられることが明らかとなった。RT-PCR法を用いた肝組織中mRNA発現の検討の結果も蛋白発現の検討結果とほぼ一致した。 マウス培養胆管細胞を用いた検討では、TNF-αなどのサイトカイン添加や酸化ストレスによりTFF1〜3とDMBT1,HGF関連因子HAI-1の発現亢進が見られた。また、酸化ストレスは培養マウス胆管細胞に細胞老化を誘導すること、この時、p16^<INK4a>抑制因子Bmi1発現低下と細胞老化関連p21^<WAF1/Cip1>,p16^<INK4a>の発現亢進が見られることが明らかとなった。<br />The impaired regeneration of biliary mucosa may be related to the pathogenesis of bile duct loss in vanishing bile duct syndrome. We examined immunohistochemically the expression of trefoil factor family (TFF)-1,2,3, a putative receptor for TFF2:DMBT1, hepatocytes growth factor (HGF) related factors (HGFA,HAI-1,cMET) and the involvement of cellular senescence in intrahepatic bile ducts in the livers taken form the patients with vanishing bile duct syndrome (n=45) including primary biliary cirrhosis (PBC) and control livers (n=65). In intrahepatic biliary system, the site-characteristic distribution of TFF1-3 was seen and TFF1, 3 and TFF2 play a role in the mucosal repair in large and small intrahepatic bile ducts, respectively. The expression of TFF2, DMBT1 and HAI-1 was increased in the damaged bile ducts in PBC. Furthermore, the biliary epithelial cells showed the features for cellular senescence such as the increased expression of p16^<INK4a> and p21^<WAF1/Cip> in the damaged bile ducts in PBC and in the livers of chronic allograft rejection. The decreased expression of bmi1, a represser of p16^<INK4a> was involved in the cellular senescence of biliary epithelial cells. The mRNA expression of these factors was in accord with the protein expression detected by immunohistochemistry. The oxidative stress and several cytokines such as TNF-alpha increased the expression of TFFs and HAI-1 in cultured mouse biliary epithelial cells. In addition, oxidative stress decreased the expression of bmi1, increased the expression of p16^<INK4a> and p21^<WAF1/Cip> and induced cellular senescence in cultured mouse biliary epithelial cells. Taken together, TFF-1,2,3 and HGF related factors were involved in the mucosal repair system in the intrahepatic biliary system as well as in the gastrointestinal tracts. The cellular senescence of biliary epithelial cells may be a main cause for the impaired regeneration and following bile duct loss in vanishing bile duct syndrome.<br />研究課題/領域番号:15590297, 研究期間(年度):2003–2005<br />出典：「肝内胆管消失症候群における胆管再生・修復不全の分子機構の解析」研究成果報告書 課題番号15590297 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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