标题：PAD4 selective inhibitor TDFA protects lipopolysaccharide-induced acute lung injury by modulating nuclear p65 localization in epithelial cells
作者：Zhao X.; Gu C.; Wang Y.
作者机构：[Zhao, X] Department of Anesthesia and Perioperative Medicine, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 更多
通讯作者地址：[Wang, Y] Department of Anesthesia and Perioperative Medicine, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong UniversityChina;
关键词：Acute lung injury; Epithelium; Inflammatory cytokine; Protein arginine deiminase 4; Transcription factor p65
摘要：Protein arginine deiminase 4 (PAD4) serves a critical role in differentiation, development and apoptosis through gene regulation and has emerged as a potential therapeutic target for the treatment of various diseases. However, the roles of PAD4 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remain largely unknown. To investigate the roles of PAD4 during LPS-induced ALI, the present study detected the trend of PAD4 expression in the lung tissues of ALI mice. Subsequently, the efficiency of TDFA on PAD4 and citrullinated H3 histone were detected. And then, histology, the wet/dry weight ratio, survival rate, activated cells infiltration, oxidative stress levels, tight junction proteins and proinflammatory cytokine expression were detected. In addition, the level of transepithelial electrical resistance (TEER) was assessed. Finally, the level of nuclear P65, total phosphorylated P65 and P65 were measured in vivo and in vitro. The results showed that PAD4 expression was upregulated in the lung tissues of LPS-induced ALI. TDFA efficiently decreased the severity of the lung edema, attenuated the severity of pulmonary injury and improved the survival rate following lethal LPS administration. Besides, TDFA reduced activated cells infiltration and suppressed inflammation related parameters, including proinflammatory cytokines production (TNF-α, IL-6 and IL-1β) and oxidative stress (MDA, GSH and SOD). Furthermore, TDFA reversed the TEER downregulation tendency and tight junction proteins (ZO-1, Occludin, Claudin-4) levels that represent the integrity of alveolar epithelium. Eventually, TDFA exerts its protective roles through modulating nuclear localization of transcription factor NF-κB P65 in epithelial cells. Taken together, these results indicate that PAD4 inhibition may serve as a promising therapeutic approach for LPS-induced ALI. © 2020