载脂蛋白ApoA-I模拟多肽D-4F对尘肺纤维化的作用及机理研究

As a common and comprehensive occupational disease, pneumoconiosis causes severe damage to the overall health of laboring force, poses serious public health issues, and undermines national economic growth as well as the stability of society. The main pathologic feature of pneumoconiosis is the consistent and progressive pulmonary fibrosis, which so far cannot be inverted or cured by all known possible means. Recent exciting researches suggested that apolipoprotein A-I(ApoA-I) in the human serum has astonishing effects of deferring the process of pulmonary fibrosis and reducing the size of mature fibrotic nodules in the lung of rat experimental silicosis model. However, the absorption and administration of ApoA-I was hindered due to the complex protein structure and large molecular size, therefore limiting the utilization and application of ApoA-I. In addition, the cellular and molecular mechanism of ApoA-I against silicosis is never elaborated. Fortunately, apolipoprotein mimic peptide D-4F possesses the key features and functions of ApoA-I, including anti-inflammatory properties and anti-atherosclerosis effect. When treating atherosclerosis, D-4F was shown to be safe for human administration. Moreover, D-4F is a hydrophilic small size molecule which consists only 18 D-type amino acids, leading to high absorbability and excellent pharmacokinetic. Although D-4F is an ideal candidate to resolve lung fibrotic nodules in silicosis, there is no documented or ongoing research focusing on investigating the effects and mechanisms of D-4F against pulmonary fibrosis in silicosis. The development and processing of pulmonary fibrosis involve a series of events, including epithelial mesenchymal transition (EMT) of alveolar epithelial cell, differentiation and alternative activation of inflammatory cells (M2 type macrophage), as well as fibrotic collagen deposition. Therefore, this proposed research will evaluate the effects of D-4F on these vital events during pulmonary fibrosis, by utilizing a variety of cellular and molecular biotechnologies such as targeted gene transcription and protein expression analysis. Furthermore, the current research will also establish silicosis rat model and perform histological analysis, in order to understand the substantial effects of D-4F on lung fibrotic nodules in silicosis. The results of this research will provide theoretical basis to better understand the general mechanism of D-4F and ApoA-I against silicosis, and offer a high potential solution in treating silicosis. More importantly, this innovative research may serve as an avant garde inspiration in tackling other fibrosis related interstitial lung diseases, including those caused by the haze of dust particle pollution, thereby improving the overall quality of national public health.

尘肺是常见职业病和重大公共卫生难题，严重损害劳动人民健康，影响国家经济发展与社会稳定。尘肺以进行性肺纤维化为特征，目前缺乏有效逆转治疗手段。最近研究显示血浆载脂蛋白ApoA-I 能缩小动物矽肺模型纤维结节，不过其蛋白结构局限了吸收和给药，作用机理也不明确。载脂蛋白模拟多肽D-4F具备ApoA-I的特性和功能，易于吸收且无毒副作用，或能更好地逆转肺纤维化，但尚无研究报道D-4F对矽肺纤维化的作用及机理。肺纤维化涉及肺泡上皮细胞间质转化、炎性细胞分化、纤维胶原沉积等环节，项目利用细胞分子技术分析标志基因转录和蛋白表达，重点研究D-4F对上述环节的影响，通过动物矽肺模型和组织学分析，考察D-4F抗肺纤维化的效果，对揭示D-4F和ApoA-I作用机理意义重大。研究成果不仅能为矽肺机理认知和治疗方法带来突破性进展，还能为治疗其他纤维化间质性肺病提供理论依据和创新思路，为提高我国公共卫生水平奠定基础。

尘肺是我国危害最严重的职业病之一，受到政府和人民群众的广泛关注。尘肺以持续进行性肺纤维化为特征，尚缺乏有效逆转治疗手段。最近研究显示，人载脂蛋白ApoA-I能缩小尘肺小鼠的肺纤维结节，而多肽D-4F不仅具备ApoA-I特性还可缓解小鼠哮喘模型炎性反应，然而尚无研究报道D-4F对尘肺纤维化的作用及机理。肺纤维化机制涉及肺泡上皮细胞间质转化(EMT)、炎性细胞分化、纤维胶原蛋白沉积等环节，本项目利用多种细胞分子生物技术，分析靶基因转录和蛋白表达，重点研究D-4F对这些环节的影响。项目关键数据揭示了D-4F能抑制巨噬细胞向促纤维化的M2型转化，并降低促纤维化因子TGF-β1的表达，能延缓TGF-β1诱导的人肺泡上皮细胞A549的EMT进程，并减少TGF-β1刺激下纤维胶原蛋白的表达和分泌。此外，本项目还通过建立小鼠肺损伤模型，分析了大气颗粒物粉尘刺激下小鼠肺灌洗液转录组学变化。本项目的研究成果不仅有助于理解尘肺发病机制并改善肺纤维化治疗手段，还能为对抗包括慢性阻塞性肺疾病和支气管哮喘在内的其他呼吸道疾病提供理论依据和创新思路，为提高我国的公共卫生水平奠定基础。

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