Alteration in the transcriptome of the lung during TGFα-induced pulmonary fibrosis

Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of stromal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent animals models generated in our lab demonstrate clinical phenotypes seen in human fibrotic disease. The mouse model of transforming growth factor-α (TGFα)-induced fibrosis include conditionally expressing TGFα in the lung epithelium under control of the CCSP promoter driving rtTA expression (CCSP/TGFα). This allow the TGFα is only expressed in airway and alveolar epithelial cells and only when mice fed doxycycline (Dox). Similar to PF in humans, TGFα mice on Dox developed a progressive and extensive adventitial, interstitial and pleural fibrosis with a decline in lung mechanics. Thus, the TGFα transgenic mouse is a powerful model to determine lung cell-specific molecular signatures involved in pulmonary fibrosis. In this study, we sought to determine changes in the transcriptome during TGFα-induced pulmonary fibrosis. Our results showed that several pro-fibrotic genes increased in the lungs of TGFα mice. This study demonstrates that WT1 network gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a critical regulator fibrotic lung disease.

肺纤维化（Pulmonary fibrosis，PF）与多种慢性肺部疾病相关，包括系统性硬化症（Systemic sclerosis，SSc）、特发性肺纤维化（Idiopathic Pulmonary Fibrosis，IPF）及囊性纤维化（Cystic Fibrosis，CF），此类疾病的特征为间质细胞进行性蓄积与瘢痕组织形成。肺纤维化是肺泡损伤引发的失调性应答，可导致肺功能进行性下降，且对现有药物治疗难治。气道上皮细胞、肺泡上皮细胞及间质细胞均可参与肺纤维化的发生发展，但介导其病理生理过程的细胞特异性通路与基因调控网络仍未明确。近期本实验室构建的动物模型可复现人类纤维化疾病的临床表型。转化生长因子-α（TGFα）诱导纤维化的小鼠模型，是在CCSP启动子驱动rtTA表达的调控系统下，于肺上皮细胞中条件性表达TGFα的模型（CCSP/TGFα）。该模型仅在小鼠饲喂多西环素（Dox）时，才可于气道上皮细胞与肺泡上皮细胞中表达TGFα。与人类肺纤维化相似，饲喂多西环素的TGFα转基因小鼠会出现进行性、广泛性的外膜、间质及胸膜纤维化，并伴随肺力学功能下降。因此，该TGFα转基因小鼠是探究肺纤维化相关肺细胞特异性分子特征的优质研究模型。本研究旨在探究TGFα诱导肺纤维化过程中转录组的动态变化。研究结果显示，TGFα小鼠肺部的多种促纤维化基因表达水平显著上调。本研究证实，WT1基因网络的变化与纤维化及肌成纤维细胞蓄积密切相关，其或可成为纤维化性肺疾病的关键调控因子。