Quan Meiyu, Guo Qiang, Yan Xihua, Yu Chenhua, Yang Linglong, Zhang Yuting, Li Jiaqi, Weng Qiongxia, Liu Bin, Li Quan, Dong Li, Chen Junjie, Lou Zhenkun, Jin Xuru, Chen Chengshui, Zhang Jin-San
Zhejiang Key Laboratory of Interventional Pulmonology; Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Chin Med J Pulm Crit Care Med. 2024 Dec 12;2(4):265-278. doi: 10.1016/j.pccm.2024.11.004. eCollection 2024 Dec.
Necroptosis is a form of programmed cell death resulting in tissue inflammation due to the release of intracellular contents. Its role and regulatory mechanism in the context of acute lung injury (ALI) are unclear. Parkin (Prkn), an E3 ubiquitin ligase, has recently been implicated in the regulation of necroptosis. In this study, we aimed to investigate the role and mechanism of Parkin in the process of ALI.
Lipopolysaccharides (LPS)-induced mouse ALI model was utilized, and the pathological changes in lung tissues were characterized. To elucidate the roles of Parkin and necroptosis in this context, mixed lineage kinase domain-like () knockout mice, conditional knockout mice, and the necroptosis inhibitor were employed. Additionally, alveolar type 2 (AT2) cell-specific Parkin deletion and lineage-tracing mice were introduced to explore the specific roles and mechanisms of Parkin in AT2 cells.
A dose-dependent increase in Parkin expression in mouse lung tissues following LPS administration was observed, correlating with a shift from epithelial apoptosis to necroptosis. Notably, depletion of MLKL significantly mitigated the pathological changes associated with ALI, particularly the inflammatory response. Conversely, the deletion of Parkin exacerbated the injury pathology, significantly enhancing necroptosis, particularly in AT2 cells. This led to increased inflammation and post-LPS fibrosis. However, treatment with GSK872, a necroptosis inhibitor, substantially mitigated the phenotype induced by Parkin deletion. Importantly, Parkin deletion impaired the proliferation and differentiation of AT2 cells into AT1 cells.
These findings underscore the multifaceted role of Parkin in the progression of lung injury, inflammation, and fibrosis through the regulation of AT2 cell necroptosis. Therefore, Parkin may hold potential as a therapeutic target for managing lung injury and fibrosis.
坏死性凋亡是一种程序性细胞死亡形式，由于细胞内物质的释放导致组织炎症。其在急性肺损伤（ALI）中的作用和调节机制尚不清楚。帕金（Prkn）是一种E3泛素连接酶，最近被认为参与坏死性凋亡的调节。在本研究中，我们旨在探讨帕金在ALI过程中的作用和机制。
利用脂多糖（LPS）诱导的小鼠ALI模型，并对肺组织的病理变化进行表征。为了阐明帕金和坏死性凋亡在此背景下的作用，使用了混合谱系激酶结构域样（）敲除小鼠、条件性敲除小鼠和坏死性凋亡抑制剂。此外，引入肺泡Ⅱ型（AT2）细胞特异性帕金缺失和谱系追踪小鼠，以探讨帕金在AT2细胞中的具体作用和机制。
观察到LPS给药后小鼠肺组织中帕金表达呈剂量依赖性增加，这与从上皮细胞凋亡向坏死性凋亡的转变相关。值得注意的是，MLKL的缺失显著减轻了与ALI相关的病理变化，特别是炎症反应。相反，帕金的缺失加剧了损伤病理，显著增强了坏死性凋亡，特别是在AT2细胞中。这导致炎症增加和LPS后纤维化。然而，用坏死性凋亡抑制剂GSK872治疗可显著减轻帕金缺失诱导的表型。重要的是，帕金缺失损害了AT2细胞增殖并分化为AT1细胞。
这些发现强调了帕金通过调节AT2细胞坏死性凋亡在肺损伤、炎症和纤维化进展中的多方面作用。因此，帕金可能具有作为治疗肺损伤和纤维化的治疗靶点的潜力。
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