LYRM03, an ubenimex derivative, attenuates LPS- induced acute lung injury in mice by suppressing the TLR4 signaling pathway  

作　　者：Hui-qiong HE Ya-xian WU Yun-juan NIE Jun WANG Mei GE Feng QIAN 

机构地区：[1]Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China [2]Shanghai Laiyi Center for Biopharmaceutical R&D Co, Ltd Shanghai Zhangjiang Hi-tech Park, Shanghai 201203, China [3]Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 220012, China [4]Department of Life Sciences, Bengbu Medical College, Bengbu 233030, China

出　　处：《Acta Pharmacologica Sinica》2017年第3期342-350,共9页中国药理学报（英文版）

基　　金：Acknowledgements This work was supported by grants from the National Natural Science Foundation of China （No 81373424, 81573438, and 81401302）, and the Specialized Research Fund for the Doctoral Program of Higher Education of China （No 20130073120108）.

摘　　要：Toll-like receptor 4 （TLR4）-mediated signaling plays a critical role in sepsis-induced acute lung injury （ALl）. LYRM03 （3-amino-2-hydroxy 4-phenyl-valyl-isoleucine） is a novel derivative of ubenimex, a widely used antineoplastic medicine. We previously found that LYRM03 has anti-inflammatory effects in cecal ligation puncture mouse mode induced ALl in mice. LPS-induced ALl mouse model was established , In this study we determined whether LYRMO3 attenuated LPS- by challenging the mice with intratracheal injection of LPS （5 mg/kg）, which was subsequently treated with LYRMO3 （10 mg/kg, ip）. LYRMO3 administration significantly alleviated LPS-induced lung edema, inflammatory cell （neutrophils and macrophages） infiltration and myeloperoxidase （MPO） activity, decreased pro-inflammatory and chemotactic cytokine （TNF-α, IL-6, IL-1β, MIP-2） generation and reduced iNOS and COX-2 expression in the lung tissues. In cultured mouse alveolar macrophages in vitro, pretreatment with LYRMO3 （100 pmoVL） suppressed LPS-induced macrophage activation by reducing Myd88 expression, increasing IKB stability and inhibiting p38 phosphorylation. These results suggest that LYRMO3 effectively attenuates LPS-induced ALl by inhibiting the expression of pro-inflammatory mediators and Myd88-dependent TLR4 signaling pathways in alveolar macrophages. LYRMO3 may serve as a potential treatment for sepsis-mediated lung injuries.Toll-like receptor 4 （TLR4）-mediated signaling plays a critical role in sepsis-induced acute lung injury （ALl）. LYRM03 （3-amino-2-hydroxy 4-phenyl-valyl-isoleucine） is a novel derivative of ubenimex, a widely used antineoplastic medicine. We previously found that LYRM03 has anti-inflammatory effects in cecal ligation puncture mouse mode induced ALl in mice. LPS-induced ALl mouse model was established , In this study we determined whether LYRMO3 attenuated LPS- by challenging the mice with intratracheal injection of LPS （5 mg/kg）, which was subsequently treated with LYRMO3 （10 mg/kg, ip）. LYRMO3 administration significantly alleviated LPS-induced lung edema, inflammatory cell （neutrophils and macrophages） infiltration and myeloperoxidase （MPO） activity, decreased pro-inflammatory and chemotactic cytokine （TNF-α, IL-6, IL-1β, MIP-2） generation and reduced iNOS and COX-2 expression in the lung tissues. In cultured mouse alveolar macrophages in vitro, pretreatment with LYRMO3 （100 pmoVL） suppressed LPS-induced macrophage activation by reducing Myd88 expression, increasing IKB stability and inhibiting p38 phosphorylation. These results suggest that LYRMO3 effectively attenuates LPS-induced ALl by inhibiting the expression of pro-inflammatory mediators and Myd88-dependent TLR4 signaling pathways in alveolar macrophages. LYRMO3 may serve as a potential treatment for sepsis-mediated lung injuries.

关 键 词：LYRMO3 UBENIMEX LPS acute lung injury alveolar macrophage pro-inflammatory cytokines toll-like receptor 4 MYD88 IKB P38 

分 类 号：R[医药卫生]