The selective Nlrp3 inflammasome inhibitor Mcc950 attenuates lung ischemia-reperfusion injury

Journal Article · Sat Sep 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.08.089· OSTI ID:23103561

Xu, Kai-Ying ^[1]; Wu, Chuang-Yan ^[1]; Tong, Song ^[1]; Xiong, Peng ^[2]; Wang, Si-Hua ^[1]

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1. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 (China)
2. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 (China)

Highlights: • The Nlrp3 inflammasome is activated by ROS during lung ischemia-reperfusion. • Mcc950 blocks Nlrp3 inflammasome activation and protects against lung ischemia-reperfusion injury. • The mechanism of Mcc950 is partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Lung ischemia-reperfusion (IR) occurs in many circumstances and leads to impaired lung function. The NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) inflammasome is reportedly activated during lung IR. Mcc950 is a recently developed Nlrp3 inhibitor. The aim of our study was to test the efficacy of Mcc950 on lung IR injury and to investigate the role of reactive oxygen species (ROS) in Nlrp3 inflammasome activation using a murine lung IR model. The results of the current study confirmed that Nlrp3 was upregulated and activated during lung IR, and inhibiting oxidative stress by the ROS scavenger edaravone attenuated Nlrp3 inflammasome activation. Mcc950 pretreatment significantly alleviated IR-induced lung injury by reducing production of the proinflammatory cytokines Il-1β and Il-18 and inhibiting neutrophil infiltration and cell apoptosis. Protein coimmunoprecipitation revealed that Mcc950 partially blocked the interaction between Nlrp3 and Nek7 (NimA-related protein kinase 7). Therefore, we conclude that ROS-dependent activation of the Nlrp3 inflammasome contributed to lung IR injury. Mcc950 significantly reduced lung IR injury by blocking Nlrp3 inflammasome activation, and the mechanism was partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Thus, Mcc950 is a promising treatment for the prevention of lung IR injury.

• OSTI ID: 23103561
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 503; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
INFLAMMATION
ISCHEMIA
LUNGS
LYMPHOKINES
NEUTROPHILS
PHOSPHOTRANSFERASES