DNA repair enzyme OGG1 promotes alveolar progenitor cell renewal and relieves PM2.5-induced lung injury and fibrosis
DNA repair enzyme OGG1 promotes alveolar progenitor cell renewal and relieves PM2.5-induced lung injury and fibrosis
复制标题
DNA修复酶OGG1促进肺泡祖细胞更新并减轻PM2.5引起的肺损伤和纤维化
DOI：
10.1016/j.ecoenv.2020.111283
复制
发表时间：
2020-12-01
影响因子：
6.8
通讯作者：
Pan, Qingjun
中科院分区：
文献类型：
--
作者：
Yang, Lawei;Liu, Gang;Pan, Qingjun
细颗粒物（PM2.5）空气污染增加了慢性呼吸道疾病的风险，如特发性肺纤维化（IPF），其特征是间质性肺的非特异性炎症和胶原纤维的广泛沉积。2型肺泡上皮细胞（AEC 2）是成人肺中的肺泡干细胞，通过复杂的信号传导促进肺修复过程。我们的前期研究表明，OGG 1是一种DNA修复酶，在保护细胞免受PM2.5诱导的氧化损伤和凋亡中发挥重要作用，但OGG 1在AEC 2s增殖和自我更新中的作用尚不清楚。本研究构建了OGG 1（-/）（-）小鼠模型，在体内研究OGG 1对PM2.5诱导的肺纤维化和肺损伤的影响及其机制。我们通过流式细胞术和克隆形成检测PM2.5损伤后OGG 1过表达或OGG 1敲除的AEC 2的增殖和自我更新。我们观察到，敲除OGG 1加重了PM2.5损伤小鼠的肺纤维化、氧化应激和AEC 2细胞死亡。此外，OGG 1是PM2.5损伤后AEC 2增殖和更新所必需的。OGG 1过表达通过抑制PM2.5介导的氧化应激和NF-κ B信号过度激活促进体外AEC 2增殖和自我更新。此外，NF-κ B抑制剂促进PM2.5损伤后OGG 1缺陷型AEC 2s细胞的增殖和自我更新，并减轻PM2.5诱导的小鼠肺纤维化和损伤。这些数据证实OGG 1是NF-κ B信号的调节因子，用于调节AEC 2细胞增殖和自我更新，并表明抑制NF-κ B信号通路可能是OGG 1低表达IPF患者的潜在治疗策略。
Fine particulate matter (PM2.5) airborne pollution increases the risk of chronic respiratory diseases, such as idiopathic pulmonary fibrosis (IPF), which is characterized by non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers. Type 2 alveolar epithelial cells (AEC2s) are alveolar stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that OGG1, a kind of DNA repair enzyme, have a critical role in protecting cells from oxidative damage and apoptosis induced by PM2.5, but the contribution of OGG1 in proliferation and self-renewal of AEC2s is not known. Here, we constructed OGG1(-/)(-) mice to test the effect and mechanism of OGG1 on PM2.5-induced pulmonary fibrosis and injury in vivo. We detected proliferation and self-renewal of OGG1 overexpression or OGG1 knockout AEC2s after PM2.5 injury by flow cytometry and clone formation. We observed that knockout of OGG1 aggravated pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, OGG1 is required for the proliferation and renewal of AEC2s after PM2.5 injury. Overexpression of OGG1 promotes the proliferation and self-renewal of AEC2s by inhibiting PM2.5-mediated oxidative stress and NF-kappa B signaling hyperactivation in vitro. Furthermore, NF-kappa B inhibitors promoted proliferation and self-renewal of OGG1-deficient AEC2s cells after PM2.5 injury, and attenuated PM2.5-induced pulmonary fibrosis and injury in mice. These data establish OGG1 as a regulator of NF-kappa B signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that inhibition of the NF-kappa B signaling pathway may represent a potential therapeutic strategy for IPF patients with low-expression of OGG1.