PMID- 32795894 OWN - NLM STAT- MEDLINE DCOM- 20210608 LR - 20210608 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 88 DP - 2020 Nov TI - Cyclic helix B peptide alleviates sepsis-induced acute lung injury by downregulating NLRP3 inflammasome activation in alveolar macrophages. PG - 106849 LID - S1567-5769(20)30926-7 [pii] LID - 10.1016/j.intimp.2020.106849 [doi] AB - Acute lung injury (ALI) exhibits high clinical morbidity and mortality rates. Our previous study has indicated that the novel proteolysis-resistant cyclic helix B peptide (CHBP) exerts an anti-inflammatory effect in mice with AKI. In the present study, we evaluated the effect of CHBP in an in vivo sepsis-induced ALI model and in vitro using lipopolysaccharide (LPS) and ATP stimulated bone marrow-derived macrophages (BMDMs). For in vivo experiments, mice were randomly divided into three groups: 1) sham; 2) LPS; and 3) LPS + CHBP (n = 6). All relevant data were collected after 18 h. Following CHBP treatment, the lung function of the mice was significantly improved compared to the LPS group. CHBP administration inhibited interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha production at both the protein and mRNA levels. Additionally, following CHBP treatment, the population of pulmonary macrophages decreased. Simultaneously, the proportion of caspase-1-activated alveolar macrophages was also decreased after CHBP treatment. The protein levels of NLRP3 and cleaved caspase-1 were attenuated in the lung tissue following CHBP treatment. In in vitro experiments, CHBP treatment decreased NLRP3 inflammasome expression and downstream IL-1beta secretion, consistent with the in vivo results. In addition, CHBP reversed nuclear factor (NF)-kappaB and I-kappaB phosphorylation with a significant dose-dependent effect. Therefore, these findings suggest the potential of CHBP as a therapeutic agent in sepsis-induced ALI owing to inhibition of the NLRP3 inflammasome via the NF-kappaB pathway in macrophages. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Zhang, Xue-Peng AU - Zhang XP AD - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. FAU - Zhang, Wei-Tao AU - Zhang WT AD - Department of Urology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China; Shanghai Key Laboratory of Organ Transplantation, No. 179 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. FAU - Qiu, Yue AU - Qiu Y AD - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. FAU - Ju, Min-Jie AU - Ju MJ AD - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. FAU - Yang, Cheng AU - Yang C AD - Department of Urology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China; Shanghai Key Laboratory of Organ Transplantation, No. 179 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. FAU - Tu, Guo-Wei AU - Tu GW AD - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China. Electronic address: tu.guowei@zs-hospital.sh.cn. FAU - Luo, Zhe AU - Luo Z AD - Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, People's Republic of China; Department of Critical Care Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, No. 668 Jinghu Road, Huli District, Xiamen 361015, People's Republic of China. Electronic address: luo.zhe@zs-hospital.sh.cn. LA - eng PT - Journal Article DEP - 20200811 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Cytokines) RN - 0 (I-kappa B Proteins) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Peptide Fragments) RN - 11096-26-7 (Erythropoietin) RN - 147257-52-1 (Nfkb1 protein, mouse) RN - EC 3.4.22.36 (Casp1 protein, mouse) RN - EC 3.4.22.36 (Caspase 1) SB - IM MH - Acute Lung Injury/*drug therapy/etiology/immunology MH - Animals MH - Caspase 1/metabolism MH - Cells, Cultured MH - Cytokines/drug effects/genetics/metabolism MH - Down-Regulation/drug effects MH - Erythropoietin/chemistry MH - I-kappa B Proteins/metabolism MH - Inflammasomes/genetics/metabolism MH - Lipopolysaccharides/toxicity MH - Lung/drug effects/pathology MH - Macrophages MH - Macrophages, Alveolar/*immunology/metabolism MH - Male MH - Mice, Inbred C57BL MH - NF-kappa B p50 Subunit/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism MH - Peptide Fragments/*pharmacology/therapeutic use MH - Sepsis/*complications MH - Signal Transduction/drug effects OTO - NOTNLM OT - Acute lung injury OT - Caspase-1 OT - Cyclic helix B peptide OT - NF-kappaB OT - NLRP3 EDAT- 2020/08/17 06:00 MHDA- 2021/06/09 06:00 CRDT- 2020/08/16 06:00 PHST- 2020/03/26 00:00 [received] PHST- 2020/07/13 00:00 [revised] PHST- 2020/07/26 00:00 [accepted] PHST- 2020/08/17 06:00 [pubmed] PHST- 2021/06/09 06:00 [medline] PHST- 2020/08/16 06:00 [entrez] AID - S1567-5769(20)30926-7 [pii] AID - 10.1016/j.intimp.2020.106849 [doi] PST - ppublish SO - Int Immunopharmacol. 2020 Nov;88:106849. doi: 10.1016/j.intimp.2020.106849. Epub 2020 Aug 11.