MiR-21和miR-30a调控肺代偿性生长的血管生成的机制研究

Compensatory lung growth after lung resection has been reported in many animal models and humans.Compensatory lung growth has been well described as a phenomenon, but still little is known about the nature, extent, and modulation of such growth. We found new vessles in the compensatory lung growth tissue, but there has been little research on the details of angiogenesis or abnormally dilated vessels in compensatory lung growth nor on the cellular or mediator aetiology of such changes. MicroRNAs (miRNAs) are a class of endogenous, small, non-coding RNAs that control gene expression by acting on target mRNAs for promoting either their degradation or translational repression. There is increasing evidence that miRNAs play important roles in vascular development as well as in vascular diseases.In this study, we try to find out some important MicroRNAs ,especially miR-21, miR-30a that regulate angiogenesis in compensatory lung growth and reconfirm them.

肺切除后剩余肺组织可发生代偿性生长。项目组发现术后发生代偿性生长的肺组织相应的肺动脉和支气管动脉明显增粗，肺表面毛细血管生成显著，提示肺代偿性生长的同时也存在血管生成，但详细机制未明。项目组还发现代偿性生长的肺组织MicroRNAs呈差异表达，分子验证实验确证了miR-21和miR-30a在代偿性生长的肺组织中表达差异的正确性，生物信息学初步分析表明候选miRNAs作用靶点与血管生成密切相关，提示候选miRNAs可能参与肺代偿性生长中血管生成的调控，但候选miRNAs临床意义、功能与机制有待深入研究。在前期研究基础之上，本项目拟研究候选miRNAs调控肺代偿性生长血管生成的生物学功能；考察候选miRNAs作用靶点与调节机制，深入剖析候选miRNAs体内作用分子机制与临床功能，从而阐明MicroRNAs在肺切除术后肺代偿性生长中血管生成的生物学功能、机制与临床意义。

肺切除术是诊断治疗肺部良恶性疾病的基本手术方式，肺组织代偿性生长是发生在肺切除术后的重要病理生理现象，肺代偿性生长伴随着血管生成，但对于肺切除术后血管生成分子调控机制仍知之甚少。肺血管内皮细胞通过合成及释放炎症介质在肺切除术引起的急性损伤过程中扮演者重要角色。本项目中，我们建立了肺切除术后失血性休克（Hemorrhagic shock，HS）模型，发现HS通过HMGB1-RAGE信号通路促进LPS诱导的小鼠肺血管内皮细胞焦亡，HMGB1可明显增加LPS诱导的Nlrp3炎症小体激活，HMGB1内吞诱导溶酶体破裂释放catB，进而导致焦亡小体的生成以及下游caspase-1的激活，该结果阐明了肺切除术后HS促进LPS诱导的小鼠肺血管内皮细胞焦亡新机制及调控过程。另外，我们发现肺切除术后肺代偿性生长中，M1及M2型巨噬细胞数量均增加，巨噬细胞极化作用影响内皮细胞的增殖能力。此外我们还发现，我们发现组蛋白甲基转移酶G9A在NSCLC中显著上调，组蛋白甲基转移酶G9A通过抑制CASP1参与促进细胞增殖。这些研究内容为肺切除术后抑制炎症反应及肺损伤，促进肺血管内皮细胞增殖肺组织代偿性生长提供了潜在药物作用靶点。

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