WNT1-Inducible Signaling Pathway Protein 1 Contributes to Ventilator-Induced Lung Injury
WNT1-Inducible Signaling Pathway Protein 1 Contributes to Ventilator-Induced Lung Injury
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DOI：
10.1165/rcmb.2012-0127oc
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发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Zhang, Li-Ming
中科院分区：
文献类型：
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作者：
Li, Hui-Hua;Li, Quan;Zhang, Li-Ming
尽管在减少呼吸机诱导的肺损伤（VILI）方面已经取得了进展，但危重患者对VILI的敏感性可能存在差异，这表明基因-环境相互作用可能有助于个体易感性。本研究试图利用全基因组方法揭示与VILI相关的候选基因，然后对小鼠中的主要候选基因进行功能分析。测定23个小鼠品系高潮气量（HTV）通气后肺泡毛细血管通透性，并进行单倍型关联图谱绘制。在第15号染色体上发现了一个包含ArfGAP SH3结构域、锚蛋白重复和PH结构域1 （Asap1）、腺苷酸环化酶8 （Adcy8）、wnt1诱导信号通路蛋白1 （Wisp1）和N-myc下游调控蛋白1 （Ndrg1）的位点。来自已发表研究的信息指导了对Wisp1的初步评估。HTV后，敏感A/J小鼠肺WISP1蛋白升高，耐药CBA/J小鼠肺WISP1蛋白不变。抗WISP1抗体降低敏感A/ j小鼠htv诱导的肺泡毛细血管通透性，重组WISP1蛋白增加耐药CBA/J小鼠htv诱导的肺泡毛细血管通透性。htv诱导的WISP1与糖基化toll样受体（TLR） 4在A/J肺匀浆中共免疫沉淀。HTV后，WISP1在菌株匹配的对照肺中升高，但在TLR4基因靶向肺中不变。在菌株匹配小鼠的腹腔巨噬细胞中，WISP1增强了lps诱导的TNF释放，这种释放在TLR4或CD14抗原基因靶向小鼠的巨噬细胞中被抑制，在髓系分化主要反应基因88基因靶向或TLR适配分子1突变小鼠的巨噬细胞中被减弱。这些发现支持WISP1作为一种内源性信号，通过TLR4信号传导增加VILI肺泡毛细血管通透性的作用。
Although strides have been made to reduce ventilator-induced lung injury (VILI), critically ill patients can vary in sensitivity to VILI, suggesting gene-environment interactions could contribute to individual susceptibility. This study sought to uncover candidate genes associated with VILI using a genome-wide approach followed by functional analysis of the leading candidate in mice. Alveolar-capillary permeability after high tidal volume (HTV) ventilation was measured in 23 mouse strains, and haplotype association mapping was performed. A locus was identified on chromosome 15 that contained ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (Asap1), adenylate cyclase 8 (Adcy8), WNT1-inducible signaling pathway protein 1 (Wisp1), and N-myc downstream regulated 1 (Ndrg1). Information from published studies guided initial assessment to Wisp1. After HTV, lung WISP1 protein increased in sensitive A/J mice, but was unchanged in resistant CBA/J mice. Anti-WISP1 antibody decreased HTV-induced alveolar-capillary permeability in sensitive A/Jmice, and recombinant WISP1 protein increased HTV-induced alveolar-capillary permeability in resistant CBA/J mice. HTV-induced WISP1 coimmunoprecipitated with glycosylated Toll-like receptor (TLR) 4 in A/J lung homogenates. After HTV, WISP1 increased in strain-matched control lungs, but was unchanged in TLR4 gene-targeted lungs. In peritoneal macrophages from strain-matched mice, WISP1 augmented LPS-induced TNF release that was inhibited in macrophages from TLR4 or CD14 antigen gene-targeted mice, and was attenuated in macrophages from myeloid differentiation primary response gene 88 gene-targeted or TLR adaptor molecule 1 mutant mice. These findings support a role for WISP1 as an endogenous signal that acts through TLR4 signaling to increase alveolar-capillary permeability in VILI.