Tenascin-C参与肺成纤维细胞功能调控在慢阻肺气道重塑机制中的作用

小气道重塑是慢性阻塞性肺疾病的主要病理改变，肺成纤维细胞异常激活致细胞外基质（ECM）过多沉积是外周小气道重塑的主要原因。近年来发现ECM分子基质蛋白Tenascin-C (TNC)具有生物活性，参与慢阻肺气道重塑，但具体机制不详。申请人前期研究显示，慢阻肺患者血清TNC表达增加，且与疾病严重程度正相关，体外重组TNC可诱导成纤维细胞分泌和迁移能力增加。最新研究表明TNC可激活TLR4受体参与某些慢性疾病的发生发展。因此，推测TNC可影响成纤维细胞功能障碍而参与慢阻肺气道重塑过程。本研究从细胞、组织、整体等多个水平，利用siRNA等多种技术手段，探讨ECM/TNC通过激活TLR4或整合素αvβ3、α2β1等分子机制，触发成纤维细胞增殖、分泌和迁移等细胞生物学功能，最终引起气道重塑的病理生理改变，为进一步阐明慢阻肺气道重塑机制和寻找新的治疗靶点提供科学的实验依据。

Small airway remodeling is a crucial pathological change in chronic obstructive pulmonary disease (COPD), excessive deposition of extracellular matrix (ECM) caused by abnormal activation of lung fibroblasts is the main cause of peripheral airways remodeling. It has been recently considered that the matrix protein tenascin-C (TNC), as a biologically active ECM protein molecules, participated in airway remodeling of COPD, but the mechanism is unknown. Our previous studies showed that the elevated TNC in serum of patients with COPD was positively correlated with the severity of the disease, and recombinant human TNC induced the increased secretion and migration of fibroblasts. TNC participated in the development of certain chronic diseases through activate TLR4 receptors in the latest research. Therefore, we propose that the dysfunction of fibroblast induced by TNC plays a key role in the airway remodeling process of COPD. The effect of ECM/TNC on the function of fibroblast in airway remodeling is to be investigated in fibroblast, animal model and patients of COPD. In this study, using the technology of TNC knockdown including RNA interference, we attempted to explored that the role and mechanism of ECM/TNC involved in the proliferation, secretion, and migration of fibroblast via the activation of the pathway of TLR4 or integrin receptor αvβ3 and α2β1, which eventually leading to pathophysiological changes of airway remodeling in COPD. The data will to provide fundamental scientific basis for further elucidating the mechanism of airway remodeling and developing the new therapeutic target of COPD.