肺成纤维细胞（LF）异常增殖可致肺纤维化。我们发现脂多糖（LPS）可抑制LF的Thy1基因表达而使细胞发生表型转变，形成具有异常增殖能力的Thy1(-)LF，但机制不明。有研究表明组蛋白去乙酰化酶（HDAC）可降低LF组蛋白乙酰化水平并抑制Thy1基因表达，而LPS可诱导其他细胞HDAC表达和活化。我们推测LPS可能通过其受体TLR4诱导LF的HDAC活化并通过组蛋白去乙酰化过程抑制LFThy1基因表达，由此对细胞增殖发挥表观遗传调控作用。本课题先比较Thy1(+)/(-)LF在LPS作用下增殖能力的差异，随后研究LPS诱导LF表型转变及增殖的机制，重点探讨LPS经TLR4对HDAC活化、组蛋白去乙酰化和Thy1基因表达的影响，并尝试在细胞和动物中使用TLR4siRNA及HDAC抑制剂进行干预。该研究有望从表观遗传调控角度完善LPS诱导肺纤维化的发病机制，为探索该病的早期防治途径提供思路。

Lung fibroblast (LF) aberrant proliferation is associated with pulmonary fibrosis. We discovered that lipopolysaccharide (LPS) could transform LF phenotype from Thy1(+)LF to Thy1(-)LF with aberrant proliferation ability through inhibiting Thy-1 gene expression. However, the mechanism remains unknown. Some investigations revealed that histone deacetylase (HDAC) could reduce the level of histone acetylation and inhibit Thy-1 gene expression. Expression and activation of HDAC was proved to be induced by LPS in other cells. Therefore, we infer that LPS may induce HDAC activation, histone deacetylation via its receptor, TLR4, and inhibit the Thy-1 gene expression to regulate LF's proliferation. In current study, we first compared the differenct proliferative capacity between Thy1(+) and Thy1(-)LF after being challenged with LPS. And then we studied the mechanism of LPS-regulated Thy-1(+) LF phenotypic transformation and proliferation. We focused on the effect of LPS on HDAC activation, histone deacetylation and expression of Thy1 gene thorough TLR4. We also attempt to interfere above process through TLR4siRNA and HDAC inhibitor in cellular and animal model. Our study aims to elaborate the mechanism of LPS-induced pulmonary fibrosis from the prospect of epigenetic regulation, and to explore the way to prevent and control the disease at early age.