The suppressive effect of activated protein C on chronic inflammatory lung disease caused by bone marrow-derived fibroblasts

活化蛋白C对骨髓成纤维细胞引起的慢性炎症性肺病的抑制作用

• 批准号: 17590788
• 负责人: GABAZZA Esteban
• 金额: $ 2.18万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590788/
• 关键词: Activated protein C; Bone marrow; Growth factors; Lung fibrosis; Fibroblasts; Extracellular matrix; Pulmonary hypertension; Chemokines; 線維芽細胞; プロテインCインヒビター; 骨髄細胞; 細胞内伝達機構; 炎症性サイトカイン; 活性化プロテインCレセプター; 実験動物モデル

Chronic inflammatory lung diseases including pulmonary hypertension, interstitial lung diseases and pulmonary fibrosis have currently no therapy and patients with these disorders have poor prognosis. The excessive production and secretion of extracellular matrix components such as collagen, fibronectin, entactin and tenascins by fibroblasts play a fundamental role in the pathogenesis of intractable chronic inflammatory lung diseases. Recently, it has been shown that fibroblasts that accumulate in the fibrotic pulmonary tissues derived from bone marrow. However, the mechanism by which fibroblasts are activated and subsequently recruited into the lungs remains unknown. In the present study, we focused on the anti-inflammatory activity of activated protein C and evaluated whether activated protein C is able to affect the motility and recruitment of fibroblasts in the lungs and their ability to secrete components of the extracellular matrix. The results of this investigation showed that activated protein C is able to inhibit in vitro the secretion of growth factors (platelet-derived growth factor), and chemokines including macrophage inflammatory protein-la, monocyte chemoattractant protein-1 and stromal-derived growth factor-1 from fibroblasts, epithelial and endothelial cells. In vivo experiments showed that activated protein C blocks the recruitment of fibroblasts and the secretion of inflammatory cytokines from lung structural cells. Overall, this study shows that activated protein C is capable of suppressing the activation of fibroblasts, suggesting that this mechanism is responsible for the inhibitory activity of activated protein C on chronic inflammatory pulmonary diseases.

慢性炎症性肺部疾病，包括肺动脉高压、间质性肺疾病和肺纤维化，目前尚无治疗方法，患有这些疾病的患者预后较差。成纤维细胞过量产生和分泌胶原蛋白、纤连蛋白、内动蛋白和腱蛋白等细胞外基质成分在难治性慢性炎症性肺部疾病的发病机制中发挥着重要作用。最近，研究表明，纤维化肺组织中积聚的成纤维细胞来源于骨髓。然而，成纤维细胞被激活并随后募集到肺部的机制仍然未知。在本研究中，我们重点关注活化蛋白 C 的抗炎活性，并评估活化蛋白 C 是否能够影响肺部成纤维细胞的运动和募集及其分泌细胞外基质成分的能力。本研究结果表明，活化蛋白C能够在体外抑制生长因子（血小板源性生长因子）和趋化因子的分泌，包括巨噬细胞炎症蛋白-1a、单核细胞趋化蛋白-1和基质源性生长因子- 1 来自成纤维细胞、上皮细胞和内皮细胞。体内实验表明，活化的蛋白 C 可以阻止成纤维细胞的募集以及肺结构细胞炎症细胞因子的分泌。总的来说，这项研究表明活化蛋白C能够抑制成纤维细胞的活化，表明这种机制是活化蛋白C对慢性炎症性肺部疾病的抑制活性的原因。

项目成果

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• DOI: 10.2353/ajpath.2006.050610
• 发表时间: 2006-04-01
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• 作者: Burioka N;Koyanagi S;Endo M;Takata M;Fukuoka Y;Miyata M;Takeda K;Chikumi H; Ohdo S;Shimizu E;Yoichi Nishii;Michihiko Yamaguchi;Tatsuya Hayashi;Hajime Fujimoto;Naoki Kijiyama;Nishii Y;Yamaguchi M;Hayashi T;Fujimoto H;Kijiyama N;Hiroki Nakahara;Kenichi Miyamoto
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