中性细胞弹性酶激活了巨细胞的calpain,作为细胞衰竭的机制
Jonathan Ma1, Apparao B Kummarapurugu1, Shuo Zheng1
1Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Children's Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia, United States.
概括
中性粒细胞弹性酶 (NE) 在囊性纤维化 (CF) 呼吸道中损害了巨细胞的功能. 卡尔帕因抑制可以挽救这种细胞失败,这表明一种独立于CFTR的潜在治疗标.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 呼吸系统医学 呼吸系统医学
背景情况:
- 中性纤维素弹性酶 (NE) 在囊性纤维化 (CF) 呼吸道中升高,并损害巨细胞细胞形成.
- 之前的研究表明,NE增加了巨细胞中Calpain-2的释放.
- 巨细胞功能障碍有助于CF的发病.
研究的目的:
- 为了调查NE是否通过Calpain激活调解巨细胞的细胞失败.
- 阐明NE调节Calpain-2活动的机制.
- 评估Calpain抑制作为CF相关的细胞衰竭的潜在治疗策略.
主要方法:
- 用小鼠膜巨细胞 (野生型和cftr-null) 来评估Calpain抑制对NE诱导的细胞衰竭的影响.
- 来自CF和非CF受试者的人类单细胞衍生巨细胞 (hMDM) 用NE治疗.
- 卡尔帕因-2 蛋白质丰富度,卡尔帕因活性,细胞内水平 (Fluo-4 测定) 和卡尔帕斯塔丁蛋白质丰富度都使用西方斑点和活动套件进行了测量.
主要成果:
- 卡尔帕因抑制在小鼠模型中挽救了NE诱导的巨细胞细胞衰竭.
- NE增加了Calpain-2蛋白水平和hMDMs中的活性.
- NE导致卡尔帕斯塔丁降解,并在巨细胞中增加细胞内,这是卡尔帕因激活的关键机制.
结论:
- 在巨细胞中,NE激活了Calpain-2,导致CF的细胞衰竭.
- NE诱导的Calpain激活通过Calpastatin降解和/或细胞内的增加而发生.
- 卡尔帕因抑制代表了一个潜在的CFTR独立的治疗点,用于恢复CF气道中的巨细胞化.
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