Parkin deficiency aggravates inflammation-induced acute lung injury by promoting necroptosis in alveolar type Ⅱ cells  

作　　者：Meiyu Quan Qiang Guo Xihua Yan Chenhua Yu Linglong Yang Yuting Zhang Jiaqi Li Qiongxia Weng Bin Liu Quan Li Li Dong Junjie Chen Zhenkun Lou Xuru Jin Chengshui Chen Jin-San Zhang 

机构地区：[1]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 [2]School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,Zhejiang 325035,China [3]Medical Research Center,The Zhejiang Key Laboratory of Intelligent Cancer,Biomarker Discovery and Translation,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325000,China [4]Department of Pulmonary and Critical Care Medicine,The Quzhou Affiliated Hospital of Wenzhou Medical University,Quzhou People’s Hospital,Quzhou,Zhejiang 324000,China [5]Department of Oncology,Mayo Clinic,Rochester,MN 55905,USA

出　　处：《Chinese Medical Journal Pulmonary and Critical Care Medicine》2024年第4期265-278,共14页呼吸与危重症医学(英文)

基　　金：supported by the National Natural Science Foundation of China(Nos.82370085 and 82170017 to CC);funding from the Zhejiang Province Public Welfare Fund Project(No.LY24H050003);the Discipline Cluster of Oncology at Wenzhou Medical University,China(No.Z1-2023004);startup research funds from both the Quzhou Affiliated Hospital and The First Affiliated Hospital of Wenzhou Medical University。

摘　　要：Background: 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. Methods: 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 ( Mlkl ) knockout mice, Prkn 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. Results: 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 sig- nificantly 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. Conclusions: 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.

关 键 词：Acute lung injury PARKIN NECROPTOSIS Alveolar type 2(AT2)cells INFLAMMATION Fibrosis Transgenic mouse models 

分 类 号：R74[医药卫生—神经病学与精神病学]