LYRM03, an ubenimex derivative, attenuates LPS-induced acute lung injury in mice by suppressing the TLR4 signaling pathway
LYRM03, an ubenimex derivative, attenuates LPS-induced acute lung injury in mice by suppressing the TLR4 signaling pathway
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LYRM03 是一种 ubenimex 衍生物，通过抑制 TLR4 信号通路减轻 LPS 诱导的小鼠急性肺损伤
DOI：
10.1038/aps.2016.141
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发表时间：
2017-03-01
影响因子：
8.2
通讯作者：
Qian, Feng
中科院分区：
文献类型：
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作者：
He, Hui-Qiong;Wu, Ya-Xian;Qian, Feng
Toll样受体4（TLR 4）介导的信号转导在脓毒症诱导的急性肺损伤（ALI）中起关键作用。LYRM 03（3-amino-2-hydroxy 4- phenyl-valyl-isoleucine）是乌苯美司（ubenimex）的新型衍生物。我们先前发现LYRM 03在盲肠结扎穿孔小鼠模型中具有抗炎作用。在本研究中，我们确定LYRM 03是否减弱LPS诱导的小鼠ALI。通过腹腔注射LPS（5 mg/kg）攻击小鼠，随后用LYRM 03（10 mg/kg，ip）治疗，建立LPS诱导的ALI小鼠模型。LYRM 03给药显著减轻LPS诱导的肺水肿、炎性细胞（中性粒细胞和巨噬细胞）浸润和髓过氧化物酶（MPO）活性，减少促炎性和趋化性细胞因子（TNF-α、IL-6、IL-1 β、MIP-2）产生，并减少肺组织中iNOS和考克斯-2表达。在体外培养的小鼠肺泡巨噬细胞中，LYRM 03（100 μ mol/L）预处理通过降低Myd 88表达，增加I.B稳定性和抑制p38磷酸化来抑制LPS诱导的巨噬细胞活化。这些结果表明，LYRM 03通过抑制肺泡巨噬细胞中促炎介质和Myd 88依赖性TLR 4信号通路的表达来有效地减轻LPS诱导的ALI。LYRM 03可能作为脓毒症介导的肺损伤的潜在治疗。
Toll-like receptor 4 (TLR4)-mediated signaling plays a critical role in sepsis-induced acute lung injury (ALI). LYRM03 (3-amino-2-hydroxy4- 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 model. In this study we determined whether LYRM03 attenuated LPSinduced ALI in mice. LPS-induced ALI mouse model was established by challenging the mice with intratracheal injection of LPS (5 mg/kg), which was subsequently treated with LYRM03 (10 mg/kg, ip). LYRM03 administration significantly alleviated LPS-induced lung edema, inflammatory cell (neutrophils and macrophages) infiltration and myeloperoxidase (MPO) activity, decreased pro-inflammatory and chemotactic cytokine (TNF-alpha, IL-6, IL-1 beta, MIP-2) generation and reduced iNOS and COX-2 expression in the lung tissues. In cultured mouse alveolar macrophages in vitro, pretreatment with LYRM03 (100 mu mol/L) suppressed LPS-induced macrophage activation by reducing Myd88 expression, increasing I.B stability and inhibiting p38 phosphorylation. These results suggest that LYRM03 effectively attenuates LPS-induced ALI by inhibiting the expression of pro-inflammatory mediators and Myd88-dependent TLR4 signaling pathways in alveolar macrophages. LYRM03 may serve as a potential treatment for sepsis-mediated lung injuries.