PKR suppress NLRP3-pyroptosis pathway in lipopolysaccharide-induced acute lung injury model of mice

• Published in: Biochemical and biophysical research communications Vol. 519; no. 1; pp. 8 - 14
• Main Authors: Zeng, Yanjun, Qin, Qingwu, Li, Keyu, Li, Haitao, Song, Chao, Li, Yi, Dai, Minhui, Lin, Fengyu, Mao, Zhi, Li, Qian, Long, Yuan, Fan, Yifei, Pan, Pinhua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-10-2019
• Subjects: Acute lung injury; Acute Lung Injury - chemically induced; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Animals; Disease Models, Animal; Double-stranded RNA-Dependent kinase; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - metabolism; Lipopolysaccharide; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Protein Kinase Inhibitors - pharmacology; Pyroptosis; Lipopolysaccharide; Acute lung injury; NLRP3; Double-stranded RNA-Dependent kinase; Pyroptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.08.054

To explore the effect of double-stranded RNA-dependent kinase (PKR) in acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS). A mouse model of lipopolysaccharide (LPS)-induced ALI was used to evaluate the levels of phosphorylated (p)-PKR and NLRP3 in lung tissue, and the protective effects of a PKR inhibitor on lung injury. And in vitro, macrophages were incubated with LPS, with or without PKR inhibitor pre-treatment. It was observed that the levels of p-PKR protein and NLRP3 protein were significantly increased compared with those in control tissues after LPS administration. Meanwhile, treatment with PKR inhibitor decreased inflammation, injury score, wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein levels, neutrophil count in BALF, myeloperoxidase activity and expression of high-mobility group box1(HMGB1) and interleukin(IL)-1β in the lungs of LPS-challenged mice. In vitro, we demonstrated that the levels of p-PKR and NLRP3, and cell mortality rate were increased in macrophages which were incubated with LPS compared with those without LPS administration, and PKR inhibitor significantly suppressed the level of NLRP3, caspase-1, HMGB1 and IL-1β. These results indicate that PKR plays a key role in ALI through NLRP3-pyrotosis pathway and pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS.
•The role of PKR in the pathogenesis of ALI/ARDS was explored.•Inhibition of PKR protects against LPS-induced ALI by suppressing NLRP3-pyrotosis pathway.•Pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS.