Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury.
Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury.
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DOI：
10.4049/jimmunol.1400653
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发表时间：
2014-06-01
期刊：
影响因子：
--
通讯作者：
Lee PJ
中科院分区：
文献类型：
--
作者：
Zhang Y;Sauler M;Shinn AS;Gong H;Haslip M;Shan P;Mannam P;Lee PJ
高水平的吸入氧气，高氧，经常用于急性呼吸衰竭患者。高氧可加重急性呼吸衰竭，其死亡率高且无特异性治疗。我们确定了PINK 1（PTEN诱导的推定激酶1），一种线粒体蛋白，和细胞溶质先天免疫蛋白，NLRP 3，在肺和内皮细胞中的新作用。我们产生了双敲除（PINK 1 −/−/NLRP 3 −/−）以及细胞靶向的PINK 1沉默和肺靶向的过表达构建体，以明确表明PINK 1介导野生型（WT）和NLRP 3 −/−小鼠的细胞保护作用。抵抗高氧的能力与PINK 1表达成正比-PINK 1 −/−小鼠最敏感，WT小鼠在高氧后诱导PINK 1，具有中等敏感性，NLRP 3 −/−小鼠具有高基础和高氧诱导的PINK 1，最不敏感。肺内皮中PINK 1基因缺失或PINK 1沉默通过改变自噬/线粒体自噬、蛋白酶体激活、细胞凋亡和氧化剂产生增加了对高氧的易感性。
High levels of inspired oxygen, hyperoxia, are frequently used in patients with acute respiratory failure. Hyperoxia can exacerbate acute respiratory failure, which has high mortality and no specific therapies. We identified a novel roles for PINK1 (PTEN-induced putative kinase 1), a mitochondrial protein, and the cytosolic innate immune protein, NLRP3, in the lung and endothelium. We generated double knockouts (PINK1−/−/NLRP3−/−) as well as cell-targeted PINK1 silencing and lung-targeted overexpression constructs to specifically show that PINK1 mediates cytoprotection in wild type (WT) and NLRP3−/− mice. The ability to resist hyperoxia is proportional to PINK1 expression – PINK1−/− mice were the most susceptible, WT mice, which induced PINK1 after hyperoxia, had intermediate susceptibility and NLRP3−/− mice, which had high basal and hyperoxia-induced PINK1, were the least susceptible. Genetic deletion of PINK1 or PINK1 silencing in the lung endothelium increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis and oxidant generation.
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影响因子：
--
作者：
Matsuda S;Kitagishi Y;Kobayashi M
通讯作者：
Kobayashi M
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
影响因子：
5.5
作者：
Fukumoto, Jutaro;Fukumoto, Itsuko;Kolliputi, Narasaiah
通讯作者：
Kolliputi, Narasaiah
影响因子：
32.4
作者：
Sutterwala, FS;Ogura, Y;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
15.9
作者：
Zhang, Xuchen;Shan, Peiying;Lee, Patty J.
通讯作者：
Lee, Patty J.