HYAL1调控TGF-β通路在IPF肺成纤维细胞增殖与凋亡的作用机制

Hyaluronoglucosaminidase 1 (HYAL1) plays important roles in the proliferation inhibition and apoptosis induction of various tumour cells. Previous investigations have shown that hyaluronic acid (HA) stimulates fibroblasts proliferation, and promote the occurrence of idiopathic pulmonary fibrosis (IPF) through the TGF-β pathway. HYAL1 is the key enzyme for HA hydrolization, and it blocks the TGF-β1 induced cell proliferation, and promotes apoptosis, which is a promising therapeutic target of IPF. However, the molecular function of HYAL1 in the pathogenesis of IPF through regulating the TGF-β signaling pathway is still unclear. Our preliminary studies have shown that HYAL1 is a key controlling gene of IPF pathogenesis, which is significantly decreased in IPF patients’ serums. HYAL1 stimulation can inhibit lung fibroblasts proliferation and promote apoptosis. This project is going to be carried out using IPF fibroblasts and HYAL1-/- knock out mice based on the hypothesis of “HYAL1 regulates the proliferation and apoptosis of lung fibroblasts”. Our findings will illustrate the molecular basis of HYAL1 on the proliferation and apoptosis processes of IPF fibroblasts by studying the process of HA degradation, the activation of WOX1 gene expression, and the activation of Egr1-Nab2 pathway, and will also provide theoretical basis for screening novel targets for the disease diagnosis, therapy and prognosis monitoring.

透明质酸酶1（HYAL1）在抑制多种肿瘤细胞增殖和促进凋亡过程中发挥重要作用。有研究表明，透明质酸（HA）可通过TGF-β通路促进肺成纤维细胞增殖，促进特发性肺纤维化（IPF）发生。HYAL1是水解HA的关键酶，能阻碍TGF-β1诱导的细胞增殖，促进凋亡，是很有前景的IPF治疗靶点。但HYAL1在IPF发生发展中调控TGF-β通路的分子机制仍不明确。我们的前期研究显示，HYAL1是IPF发病关键制约基因，在IPF患者血清中含量明显下降，HYAL1刺激能抑制肺成纤维细胞增殖并促进凋亡。本研究拟以“HYAL1调控肺成纤维细胞增殖和凋亡”为切入点，利用IPF肺成纤维细胞和HYAL1-/-基因敲除小鼠展开研究，分别从1）降解HA；2）促进WOX1表达；3）激活Egr1-Nab2通路的角度，揭示HYAL1调控IPF肺成纤维细胞增殖与凋亡的作用机制，为临床筛选新的诊断、治疗和预后监测靶点提供理论依据。

IPF是最常见和最严重的间质性肺疾病，表现为慢性、进行性且通常为致死性的肺部纤维化。IPF形成的主要原因是肺泡上皮细胞的损伤和激活、成纤维细胞或肌成纤维细胞病灶的形成以及细胞外基质的大量堆积。探讨肺成纤维细胞增殖或凋亡对研究IPF的发病机制具有重要意义。HYAL1是细胞外基质成分中的重要成分。本研究主要研究HYAL1在IPF肺组织的表达以及HYAL1表达与肺成纤维细胞增殖或凋亡的关系，并尝试阐述HYAL1调节肺成纤维细胞增殖或凋亡能力的作用机制，特别是在此过程中HYAL1与TGFβ信号通路的作用。本研究结果显示，相对于正常肺组织，IPF肺组织的HYAL1表达显著下降，HYAL1在正常肺组织的表达主要分布在II型肺泡上皮细胞。IPF患者和正常人原代肺成纤维细胞的HYAL1在蛋白质水平的表达差异不明显。表达谱芯片分析及Real-time qPCR和Western Blot实验结果显示，HYAL1抑制HFL-1肺成纤维细胞的增殖可能通过激活BMPR2-SMAD1.5.9信号通路实现。