特发性肺间质纤维化(IPF)是一种慢性、进行性发展的肺部疾病。研究表明肺泡中的干细胞-肺泡2型（AT2）细胞衰老是肺纤维化发病机制的重要环节。线粒体功能异常引起氧化应激，促进干细胞衰老。我们前期研究表明AT2细胞线粒体Lon蛋白酶1（Lonp1）基因缺失引起小鼠模型肺纤维化加重，AT2细胞减少，但Lonp1基因是否通过调控AT2细胞衰老促进肺纤维化尚不明确。本研究以AT2细胞为切入点，利用Cre-Loxp系统构建敲除AT2细胞Lonp1基因，以博来霉素诱导肺纤维化小鼠模型。首先明确Lonp1基因是否通过线粒体调控AT2细胞衰老、上调TGF-β促进肺纤维化；其次探讨Lonp1基因是否通过线粒体氧化应激引起NAD+/SIRT下调及内质网应激（ESR），诱导AT2细胞衰老；最后明确上调NAD或抑制ESR是否改善AT2细胞衰老、下调TGF-β以减轻肺纤维化，为肺纤维化的治疗提供新的干预靶点。

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease. The molecular paradigms and pathways during lung fibrogenesis still need to be investigated. Recent studies found senescence of lung progenitor cells- alveolar type 2 (AT2) cells play a pivotal role in lung fibrogenesis. Dysfunction of mitochondria induced oxidative stress drives senescence of stem cells. Our preliminary data found inactivation of Lon protease 1 （Lonp1） in AT2 cells led to severe lung fibrosis and decreased AT2 cells in mouse models. However, it remains unclear that Lonp1 inactivation could induce senescence of AT2 cells and promote pulmonary fibrosis. In this study, we aim to construct bleomycin- induced mouse models with inactivation of Lonp1 in AT2 cells by Cre-Loxp system. Firstly, we aim to define if Lonp1 inactivation induces senescence of alveolar type 2 cells via dysfunction of mitochondria and upregulates TGF-β signaling to promote fibrosis. Secondly, we aim to determine if Lonp1 inactivation induces inhibition of NAD+/SIRT signaling and increased endoplasmic reticulum stress (ERS) via oxidative stress, which contributes to senescence of AT2 cells. Thirdly, we aim to find if upregulation of NAD or inhibition of ERS could alleviate senescence of AT2 cells and downregulate TGF-β, which provides therapeutic targets for pulmonary fibrosis.