PMID- 33675774 OWN - NLM STAT- MEDLINE DCOM- 20210630 LR - 20211204 IS - 1873-2968 (Electronic) IS - 0006-2952 (Print) IS - 0006-2952 (Linking) VI - 186 DP - 2021 Apr TI - MNK as a potential pharmacological target for suppressing LPS-induced acute lung injury in mice. PG - 114499 LID - S0006-2952(21)00095-2 [pii] LID - 10.1016/j.bcp.2021.114499 [doi] AB - Acute lung injury (ALI) or its more severe form, known as acute respiratory distress syndrome (ARDS), is characterized by an initial exudative phase, expression of proinflammatory mediators, activation of inflammatory leukocytes, and impairment of the lung endothelium and epithelium. Despite numerous, novel therapeutic strategies have been developed regarding the pathophysiology of ALI, current treatment is mainly supportive, as specific therapies have not been established in the past few decades. The MAP kinase-interacting kinases (MNK1 and MNK2) are serine threonine kinases which are activated by mitogen-activated protein kinases (MAPKs), regulate protein synthesis by phosphroylating eukaryotic translation initiation factor 4E (eIF4E). Although studies have shown that MAPKs pathway is involved in anti-inflammatory and preventing tissue injury processes, the role of MNKs in ALI has, until now, remained relatively unexplored. Here, we investigated whether partial inhibition of MAPKs pathway by targeting MNKs was effective in the prevention and treatment of ALI. C57BL6 mice were pretreated with MNK1 and MNK2 inhibitor (CGP57380, 30 mg/kg) for 30 min and then challenged with 5 mg/kg LPS for 6 h. The results showed that pretreatment with CGP57380 not only significantly attenuated LPS-induced lung wet/dry ratio, as well as protein content, total cells and neutrophils in bronchoalveolar lavage fluid (BALF), but also decreased the production of pro-inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and keratinocyte-derived chemoattractant (KC). In addition, CGP57380 was observed to significantly suppress LPS-stimulated phosphorylation of eIF4E and MAPKs in the mouse bone marrow-derived macrophages (BMDMs). The involvement of MNK2 in lung injury was further evident by MNK2 knockout mice. MNK2 deficiency resulted in the attenuated lung histopathological changes, as also reflected by reductions in neutrophil counts, and the less LPS-induced the production of IL-6, TNF-alpha and KC in mouse BALF. Taken together, these findings demonstrated for the first time that MNK inhibition could effectively reduce the LPS-induced ALI in mice, suggesting a novel and potential application for MNK-based therapy to treat this serious disease. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Gao, Jianfeng AU - Gao J AD - Center for Animal Experiment, State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. FAU - Teng, Li AU - Teng L AD - Department of Pathology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, China. FAU - Yang, Sijun AU - Yang S AD - Center for Animal Experiment, State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. FAU - Huang, Shuguang AU - Huang S AD - College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China. FAU - Li, Linrui AU - Li L AD - College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China. FAU - Zhou, Li AU - Zhou L AD - Center for Animal Experiment, State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. FAU - Liu, Guoquan AU - Liu G AD - College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China. FAU - Tang, Hongbin AU - Tang H AD - Center for Animal Experiment, State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. Electronic address: hbtang@whu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210304 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Aniline Compounds) RN - 0 (CGP 57380) RN - 0 (Lipopolysaccharides) RN - 0 (Purines) RN - EC 2.7.1.- (Mknk1 protein, mouse) RN - EC 2.7.1.- (Mknk2 protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Acute Lung Injury/chemically induced/drug therapy/*metabolism MH - Aniline Compounds/administration & dosage MH - Animals MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - Drug Delivery Systems/*methods MH - Lipopolysaccharides/*toxicity MH - Macrophages/drug effects/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Purines/administration & dosage PMC - PMC7957947 OTO - NOTNLM OT - Acute lung injury OT - CGP57380 OT - Inflammatory cytokines OT - MAPKs OT - MNK COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2021/03/07 06:00 MHDA- 2021/07/01 06:00 PMCR- 2021/03/04 CRDT- 2021/03/06 20:10 PHST- 2020/12/24 00:00 [received] PHST- 2021/02/24 00:00 [revised] PHST- 2021/02/25 00:00 [accepted] PHST- 2021/03/07 06:00 [pubmed] PHST- 2021/07/01 06:00 [medline] PHST- 2021/03/06 20:10 [entrez] PHST- 2021/03/04 00:00 [pmc-release] AID - S0006-2952(21)00095-2 [pii] AID - 114499 [pii] AID - 10.1016/j.bcp.2021.114499 [doi] PST - ppublish SO - Biochem Pharmacol. 2021 Apr;186:114499. doi: 10.1016/j.bcp.2021.114499. Epub 2021 Mar 4.