矽肺是我国发病率最高的一种尘肺病，对广大劳动者的健康造成严重损害。但迄今为止，矽肺的发病机制尚不明确，无有效的治疗药物。有研究证实，磷脂家族的1－磷酸鞘氨醇（S1P）和溶血磷脂酸（LPA）参与肝、肾、肺纤维化形成，本课题组前期研究发现矽肺大鼠模型外周血和肺泡灌洗液中LPA含量升高，LPA可促进肺纤维细胞增殖、α平滑肌肌动蛋白表达等，提示LPA可能参与矽肺病形成。磷脂家族的S1P与LPA的生物学作用相似，因此我们提出S1P和LPA及其受体可能参与矽肺病形成的假设，拟分别采用5个S1P受体和7个LPA受体的特异性抑制剂抑制相应受体功能，观察肺纤维细胞在三维胶原收缩、细胞转化和胶原合成等生物学功能的改变，进一步探索不同S1P和LPA受体在矽肺病发生过程中的作用，并进行有关信号传导的研究，为今后探索矽肺病新的治疗药物提供理论依据。为进一步证实S1P和LPA参与矽肺纤维化形成，拟测量不同期别矽肺病人血清中LPA和S1P的水平，也为探索矽肺诊断的体外标志物打下基础。

Silicosis is the highest incidence of pneumoconiosis which has done great harm to the labourer’s health. The occurrence mechanism of silicosis is still unknown and there is no effective treatment until now. Some studies have shown that the sphingolipids: Sphingosine- 1-phosphate (S1P) and Lysophosphatidic acid (LPA) have involved in the liver, kidney and lung fibrosis. Our previous studies have found that LPA levels increased in the serum and bronchoalveolar lavage fluid in the silicosis animal model. LPA could also promoted lung fibroblasts proliferation, αsmooth muscle actin expression which indicated that LPA may play an important role in the silicosis formation. The biological function of S1P is similar to that of LPA and we hypothesized that both S1P and LPA may involved in the lung fibrosis during the silicosis occurrence. We will use five S1P receptors and seven LPA receptors antagonists to inhibit the specific receptor. Some of biological effects of lung fibrosblasts, such as three dimension gel contraction, cell transformation and collagen synthesis, may change. We will explore the downstream signal transduction pathway and illustrate the molecular mechanisms of silicosis. These studies may afford for the theoretical basis of new drug therapy in the future. In order to confirm that S1P and LPA may take part in the silicosis fibrosis formation and explore the silicosis diagnosis in vitro biomarkes, we will also measure the serum LPA and S1P level of different stages silicosis patients.

矽肺是我国发病率最高的一种尘肺病，对广大劳动者的健康造成严重损害，但至今其发病机制尚未完全阐明。我们采用细胞实验和检测尘肺病人外周血中的有关磷脂水平研究1－磷酸鞘氨醇（S1P）和溶血磷脂酸（LPA）在矽肺发病过程中所起的作用。文献报道S1P和LPA参与肝、肾、肺纤维化形成。由于二氧化硅致肺纤维化作用很强，我们使用二氧化硅作用于人胚胎肺纤维细胞三维培养的方法制作矽肺细胞模型并研究矽肺的发病机制。本课题组在研究中发现S1P 和LPA 可引起肺纤维细胞三维胶原收缩、肺纤维细胞表达α平滑肌肌动蛋白、抑制细胞凋亡、促进细胞增殖和胶原合成等。S1P1/2/5受体被SiRNA基因敲除后及LPA1/3受体抑制剂（Ki1642）可抑制上述S1P和LPA的生物学作用，S1P明显增加人胚胎肺纤维细胞增殖，ERK及PI3K/Akt抑制剂（PD98059 和LY294002）可有效抑制S1P引起的细胞增殖作用。当S1P受体1、2、5被基因敲除后，细胞凋亡增加，这说明S1P和LPA参与了矽肺致肺纤维化的发病过程。主要是通过S1P1、2、5 受体和LPA1/3受体而起作用。通过检测尘肺患者血清中LPA的浓度，发现接尘组、壹期和贰期煤工尘肺组血清LPA水平明显高于健康对照组，说明S1P 和LPA在尘肺患者肺纤维化过程中发挥重要作用，为探索尘肺病发病机制和早期诊治提供了理论依据。