Mechanical Ventilation Augments Poly(I:C)-Induced Lung Injury via a WISP1-Integrin β3-Dependent Pathway in Mice
Mechanical Ventilation Augments Poly(I:C)-Induced Lung Injury via a WISP1-Integrin β3-Dependent Pathway in Mice
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DOI：
10.2119/molmed.2015.00233
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
Li, Quan
中科院分区：
文献类型：
--
作者：
Jin, Shuqing;Chen, Zhixia;Li, Quan
机械通气可以改善低氧血症，但也可能导致所谓的呼吸机诱导肺损伤（VILI）。多肌苷：多胞苷酸（聚（I: C））是天然双链RNA病毒的类似物，可诱导肺部炎症。本研究的目的是确定中度潮气量机械通气（MTV）是否会增加聚（I: C）诱导的肺损伤，如果是，其机制是什么。2 μ g/g poly（I: C）灌胃C57BL/6J型（WT）小鼠。然后随机分为MTV组（10ml /kg潮气量）和自然呼吸组。4 h后采集肺组织和支气管肺泡灌洗液（BALF）进行各项测量。我们的研究结果表明，MTV对正常肺没有明显的损伤，但对poly（I: C）诱导的肺损伤增强。wnt诱导的分泌蛋白1 （WISP1）表达水平与肺损伤一致，抗WISP1抗体处理可减轻MTV对肺损伤的放大。MTV进一步增加了poly（I: C）诱导的整合素β 3在肺中的表达。我们进行了共免疫沉淀，结果表明WISP1和β 3之间存在相互作用。WISP1显著增加了从WT小鼠分离的巨噬细胞中poly（I: C）诱导的tnf - α产生，但在β 3敲除小鼠分离的巨噬细胞中没有。与WISP1和poly（I: C）共处理可显著增加巨噬细胞胞外信号相关激酶（ERK）的磷酸化。用ERK抑制剂U0126预处理巨噬细胞，剂量依赖性地拮抗WISP1对poly（I: C）诱导的tnf - α释放的协同作用。总之，MTV以wisp1和整合素β 3依赖的方式加重poly（I: C）诱导的肺损伤，至少部分涉及ERK通路的激活。wisp1 -整合素- 3通路可能是一个新的治疗靶点。
Mechanical ventilation can improve hypoxemia, but can also cause the so-called ventilator-induced lung injury (VILI). Polyinosinic: polycytidylic acid (poly(I: C)), an analogue of natural double-strand RNA virus, can induce lung inflammation. The purpose of this study was to determine whether moderate tidal volume mechanical ventilation (MTV) augments poly( I: C)-induced lung injury, and if so, the mechanism responsible for it. Two mu g/g poly(I: C) were instilled intratracheally in C57BL/6J wide type (WT) mice. They were then randomized to MTV (10 ml/kg tidal volume) or spontaneous breathing. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4 h later for various measurements. Our results showed that MTV did not cause significant injury in normal lungs, but augmented poly(I: C)-induced lung injury. The expression level of WNT-induced secreted protein 1 (WISP1) was consistent with lung injury, and the amplification of lung injury by MTV could be alleviated by anti-WISP1 antibody treatment. MTV further increased poly(I: C)-induced integrin beta 3 expression in the lung. We performed coimmunoprecipitation, which showed there was an interaction between WISP1 and beta 3. WISP1 significantly increased poly(I: C)-induced TNF-alpha production in macrophages isolated from WT mice, but not in macrophages isolated from beta 3 knockout mice. Cotreatment with WISP1 and poly( I: C) markedly increased the phosphorylation of extracellular signal-related kinase (ERK) in macrophages. Pretreating macrophages with an ERK inhibitor, U0126, dose-dependently antagonized the synergistic effect of WISP1 on poly(I: C)-induced TNF-alpha release. In conclusion, MTV exaggerates poly(I: C)-induced lung injury in a WISP1-and integrin beta 3-dependent manner, involving, at least in part, the activation of the ERK pathway. The WISP1-integrin beta 3 pathway could be a novel therapeutic target.