Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Life Sci. 2024 Dec 1;358:123128. doi: 10.1016/j.lfs.2024.123128. Epub 2024 Oct 10.
Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood.
In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-β-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess reactive oxygen species (ROS).
Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-β, as indicated by the increased levels of p53 and p21, along with an increase in β-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-β combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-β. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo.
Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF.
特发性肺纤维化（IPF）是一种与衰老相关的疾病，其中氧化应激的增加加速了肺纤维化（PF）的进展。氧化应激加剧 PF 的具体机制尚不完全清楚。
在这项研究中，我们分别使用博来霉素（BLM）诱导的 PF 小鼠模型和 TGF-β诱导的胶原蛋白沉积细胞进行体内和体外实验。此外，我们使用了 BSO，一种谷胱甘肽合成抑制剂，来诱导过量的活性氧（ROS）。
我们的研究结果表明，ROS 产生的增加显著加剧了小鼠 PF 的发展，并增加了 A549 细胞中的胶原蛋白沉积。我们还表明，BSO 与 BLM 或 TGF-β联合处理进一步加剧了细胞衰老，表现为 p53 和 p21 水平升高，以及β-半乳糖苷酶阳性细胞增加。此外，BSO 和 BLM 或 TGF-β联合处理导致炎症反应，包括炎症细胞、炎症细胞因子和 ROS 水平显著增加。从机制上讲，我们发现 NLRP3 炎性小体在 BSO 与 BLM 或 TGF-β联合处理时被更显著地激活。NLRP3 的抑制改善了与衰老相关的表型，并降低了 p53 和 p21 的表达。此外，我们表明 N-乙酰半胱氨酸（NAC）治疗显著减轻了体内 BLM 或 BLM 加 BSO 增强的 PF。
我们的研究表明，ROS 水平的升高通过 NLRP3 介导的细胞衰老促进 PF 的发展。我们还表明，靶向氧化应激可能是治疗 PF 的有效策略。
