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

• Published in: Acta pharmacologica Sinica Vol. 38; no. 3; pp. 342 - 350
• Main Authors: He, Hui-qiong, Wu, Ya-xian, Nie, Yun-juan, Wang, Jun, Ge, Mei, Qian, Feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; Nature Publishing Group
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Acute Lung Injury - immunology; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cytokines - metabolism; Immunology; Inflammation - drug therapy; Inflammation - immunology; Inflammation - metabolism; Internal Medicine; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Male; Medical Microbiology; Mice, Inbred C57BL; Neutrophil Infiltration - drug effects; Oligopeptides - therapeutic use; Original; original-article; Pharmacology/Toxicology; Signal Transduction; Toll-Like Receptor 4 - metabolism; Vaccine; IκB; alveolar macrophage; p38; pro-inflammatory cytokines; LYRM03; ubenimex; acute lung injury; toll-like receptor 4; Myd88; LPS
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2016.141

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.