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PICK1 deficiency exacerbates sepsis-associated acute lung injury and impairs glutathione synthesis via reduction of xCT.
Qian, Meizi; Lou, Yingying; Wang, Yixiu; Zhang, Minyuan; Jiang, Qun; Mo, Yunchang; Han, Kunyuan; Jin, Shenhui; Dai, Qinxue; Yu, Yulong; Wang, Zhen; Wang, Junlu.
Affiliation
  • Qian M; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: qianmeizi1991@163.com.
  • Lou Y; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 605570569@qq.com.
  • Wang Y; Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China. Electronic address: wangyixiu1997@163.com.
  • Zhang M; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 7231934@qq.com.
  • Jiang Q; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 904510307@qq.com.
  • Mo Y; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: myc1104@163.com.
  • Han K; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 707884183@qq.com.
  • Jin S; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 491452861@qq.com.
  • Dai Q; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: 653091408@qq.com.
  • Yu Y; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: yyl@enzemed.com.
  • Wang Z; Institute of Molecular Medicine, Department of Blood Transfusion, Zhejiang Provincial People's Hospital, Hangzhou 310014, China. Electronic address: yuchen6046@163.com.
  • Wang J; Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: wangjunlu973@163.com.
Free Radic Biol Med ; 118: 23-34, 2018 04.
Article in En | MEDLINE | ID: mdl-29471107
ABSTRACT
The role of oxidative stress has been well documented in the development of sepsis-induced acute lung injury (ALI). Protein interaction with C-kinase 1 (PICK1) participates in oxidative stress-related neuronal diseases. However, its function in lung infections and inflammatory diseases is not known. We therefore sought to investigate whether PICK1 is involved in sepsis-induced ALI. Cecal ligation and puncture (CLP) was performed in anesthetized wild type (WT) and PICK1 knock out (KO, PICK1-/-) mice with C57BL/6 background. At the time of CLP, mice were given fluid resuscitation. Mouse lungs were harvested at 24 and 72 h for Western blot analysis, qRT-PCR, BALF analysis, Hematoxylin and Eosin staining, TUNEL staining, maleimide staining, flow cytometry analysis, GCL, GSH, GSSG and cysteine levels measurement. A marked elevation of PICK1 mRNA and protein level were demonstrated in lung tissue, which was accompanied by increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and consumption of glutathione (GSH). N-acetylcysteine (NAC), buthionine sulfoximine (BSO) and GSH-monoethyl ester (GSH-MEE) were injected into mice via caudal vein to regulate glutathione (GSH) level in lung. Alterations of lung GSH content induced PICK1 level change after CLP challenge. In PICK1-/- underwent with CLP, lung injury and survival were significantly aggravated compared with wild-type mice underwent with CLP. Concomitantly, CLP-induced lung cell apoptosis was exacerbated in PICK1-/- mice. The level of xCT, other than PKCα, in lung tissue was significantly lowered in PICK1-/- but not in wild type that underwent CLP surgery. Meanwhile, Nrf2 activation, which dominating xCT expression, was inhibited in PICK1-/- but not in wild type mice that underwent CLP surgery, as well. Moreover, higher level of PICK1 was detected in PBMCs of septic patients than healthy controls. Taken together, PICK1 plays a pivotal role in sepsis-induced ALI by regulating GSH synthesis via affecting the substrate-specific subunit of lung cystine/glutamate transporter, xCT.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Nuclear Proteins / Carrier Proteins / Sepsis / Amino Acid Transport System y/ / Acute Lung Injury / Glutathione Type of study: Etiology_studies / Risk_factors_studies Limits: Adult / Aged / Animals / Female / Humans / Male / Middle aged Language: En Journal: Free Radic Biol Med Journal subject: BIOQUIMICA / MEDICINA Year: 2018 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Nuclear Proteins / Carrier Proteins / Sepsis / Amino Acid Transport System y/ / Acute Lung Injury / Glutathione Type of study: Etiology_studies / Risk_factors_studies Limits: Adult / Aged / Animals / Female / Humans / Male / Middle aged Language: En Journal: Free Radic Biol Med Journal subject: BIOQUIMICA / MEDICINA Year: 2018 Document type: Article