白介素22调控TGF-β信号通道对特发性肺纤维化作用机制的研究

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. It is associated with a poor prognosis. Several retrospective longitudinal studies suggest a median survival time from 2 to 3 years from the time of diagnosis. The international committee did not find sufficient evidence to support the use of any specific pharmacologic therapy for patients with IPF. The primary effector cell in fibrosis is the myofibroblast(MF). The formation of fibroblast foci mainly constituted of MFs is the important characteristics of the pathology. Based on our studies, we discovered that the expressions of transforming growth factor β (TGF-β1) were upregulated in the lungs of IPF patients and bleomycin(BLM)-induced animals; and the expressions of interleukin 22 (IL22) were downregulated in peripheral blood of the patients with IPF. IL22 could inhibit the transdifferentiations from A549 and human embryonic lung fibroblast (HELF) cells to MFs, and suppress the expressions of TGF-β receptor 2 on the surfaces of these cells. We hypothize that IL22 could inhibit the expressions of TGF-βR on alveolar epithelial cells and fibroblasts which lead to the suppressions of Smad2/3 signal pathways and pulmonary fibrosis formations. We will investigate the role and mechanism of the myofibroblast formation inhibited by IL22 through cell cultures in our study. Through the experiments of BLM-induced and IL22R knock out animals in vivo, we want to explore the effect of TGF-β signaling on BLM-induced pulmonary inflammations and fibrosis regulated by interleukin 22, thus to provide theoretical evidences of new treatment target of IPF.

特发性肺纤维化（IPF）一种发病机制尚不明确的慢性进展性纤维化型间质性肺炎，预后差，中位生存时间仅2-3年，目前尚无明确疗效的治疗措施。肺内肌成纤维细胞（MF）为主成纤维细胞灶的形成是IPF重要的病理特征。我们研究发现，TGF-β1在IPF患者及博来霉素（BLM）诱导动物肺组织高表达，IL22在IPF患者外周血低表达；IL22可以抑制A549及人胚肺成纤维细胞（HELF）向MF转分化，并抑制细胞表面TGF-βR2的表达。我们假设IL22可以通过抑制肺泡上皮细胞及FB表面TGF-βR的表达，抑制Smad2/3信号通道，从而抑制肺纤维化的形成。本课题将通过A549及HELF细胞培养，研究IL22抑制MF形成的作用和机制；并通过BLM诱导和IL22R敲除动物模型的体内试验，探索IL22对BLM诱导的肺部炎症和纤维化的影响及对TGF-β信号通道的调节作用，为寻求IPF新的治疗靶点提供理论依据。