Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiation.
Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiation.
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DOI：
10.1186/s12989-017-0198-0
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发表时间：
2017-06-08
影响因子：
10
通讯作者：
Ma Q
中科院分区：
文献类型：
--
作者：
Dong J;Ma Q
碳纳米管（CNT）由于其独特的性质和功能而被用于多种应用。然而，许多碳纳米管已被证明会诱发实验动物肺纤维化，其中一些碳纳米管的效力比二氧化硅还要大，这引起了人们对碳纳米管暴露对人类可能产生毒性作用的担忧。有必要研究碳纳米管诱发肺纤维化的机制，以促进对碳纳米管在暴露人群中可能发生的肺部病变的理解、监测和治疗。目前的研究重点是研究骨桥蛋白（OPN）在暴露于多壁碳纳米管（MWCNT）后肺纤维化发展中的作用。通过咽部抽吸将 C57BL/6J (WT) 和 Opn 敲除 (KO) 小鼠暴露于 MWCNT，以检查 MWCNT 暴露的急性和慢性影响。在体内和体外的细胞和分子水平上分析了 OPN 的作用及其在肺纤维化发展中的作用模式。在小鼠肺部暴露于 MWCNT 的反应的急性期和慢性期，OPN 均被高度且持续地诱导。 WT 和 Opn KO 小鼠之间的比较表明，OPN 严格调节 MWCNT 诱导的肺纤维化，如 Opn KO 肺中纤维化病灶形成和肌成纤维细胞积累减少所示。在分子水平上，OPN 促进 TGF-β1 的表达和激活，刺激成纤维细胞分化为肌成纤维细胞，并增加暴露于 MWCNT 的肺和培养肺细胞中纤维基质蛋白的产生。 OPN 在 CNT 暴露的肺部中被高度诱导，并在 TGF-β1 信号激活和肌成纤维细胞分化中发挥关键作用，从而促进 MWCNT 暴露导致的纤维化发展。这项研究揭示了 OPN 依赖性促进 MWCNT 诱导肺纤维化的机制。这些发现提出了使用 OPN 作为监测 CNT 暴露的生物标志物和作为阻止纤维化发展的药物靶点的可能性。
Carbon nanotubes (CNTs) have been used in a variety of applications because of their unique properties and functions. However, many CNTs have been shown to induce lung fibrosis in experimental animals with some at a potency greater than that of silica, raising concern over possible toxic effects of CNT exposure in humans. Research into the mechanisms by which CNTs induce pulmonary fibrosis is warranted in order to facilitate the understanding, monitoring, and treatment of CNT-induced lung lesions that might occur in exposed populations. The current study focuses on investigating the role of osteopontin (OPN) in the development of lung fibrosis upon exposure to multi-walled carbon nanotubes (MWCNTs). C57BL/6J (WT) and Opn knockout (KO) mice were exposed to MWCNTs by pharyngeal aspiration to examine the acute and chronic effects of MWCNT exposure. The role of OPN and its mode of action in lung fibrosis development were analyzed at the cellular and molecular levels in vivo and in vitro. OPN was highly and persistently induced in both the acute and chronic phases of the response to MWCNT exposure in mouse lungs. Comparison between WT and Opn KO mice revealed that OPN critically regulated MWCNT-induced lung fibrosis as indicated by reduced fibrotic focus formation and myofibroblast accumulation in Opn KO lungs. At the molecular level, OPN promotes the expression and activation of TGF-β1, stimulates the differentiation of myofibroblasts from fibroblasts, and increases the production of fibrous matrix proteins in lungs and cultured lung cells exposed to MWCNTs. OPN is highly induced in CNT-exposed lungs and plays critical roles in TGF-β1 signaling activation and myofibroblast differentiation to promote fibrosis development from MWCNT exposure. This study reveals an OPN-dependent mechanism to promote MWCNT-induced lung fibrosis. The findings raise the possibility of using OPN as a biomarker to monitor CNT exposure and as a drug target to halt fibrosis development.