Injurious mechanical ventilation has been shown to directly affect pulmonary and systemic immune responses. How these responses propagate or attenuate remains unknown. The goal of this study was to further determine whether toll-like receptor (TLR) 4 and WNT1-inducible signaling pathway protein 1 (WISP1) could contribute to injurious mechanical ventilation, especially focusing on the role of macrophages during experimental ventilator-induced lung injury. A prospective, randomized, and controlled animal study was designed, and male, wild-type (WT) C57BL/6 mice, TLR4 knockout (TLR4-/-), and lyzTLR4 knockout (lyzTLR4-/-) mice aging 8~12 weeks were used. Animals were anesthetized and randomized to spontaneous breathing (SB) group or to high tidal volume (VT, 20 ml/kg) mechanical ventilation (HTV) group. Histological evaluation, alveolar-capillary permeability of Evan's blue albumin (EBA), WISP1 protein levels, macrophage inflammatory protein-2 (MIP-2), and interleukin-6 (IL-6) in plasma and bronchoalveolar lavage fluid (BALF) concentrations were analyzed. HTV group was associated with a significant increase of WISP1 and EBA ratio in C57BL/6 mice, a significant decrease of WISP1 protein levels, and a significant decrease of IL-6, MIP-2 in plasma, and BALF concentrations of pro-inflammatory cytokines in TLR4-/- and lyzTLR4-/- knockout mice. In TLR4-/- mice and lyzTLR4-/- mice, there were also significant differences between SB group and HTV group in terms of H&E score and EBA ratio and level of pro-inflammation cytokines. The entire TLR4-targeted mice could further improve various inflammatory changes and damages when compared with lyzTLR4-targeted mice. What is more, TLR4-/- mice and lyzTLR4-/- mice reacted differently to rWISP1 and/or BMMC treated. TLR4-/- mice had no response to rWISP1, while lyzTLR4-/- mice still showed drastic response to both treatments. TLR4 and WISP1, especially the former one, on macrophages could contribute to releasing of pro-inflammatory cytokines during ventilator-induced lung injury. Injurious mechanical ventilation may result in an immune response which is similar to that of infection.

中文翻译：

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巨噬细胞上的WISP1和TLR4导致呼吸机诱发的肺损伤。

有害的机械通气已显示直接影响肺部和全身的免疫反应。这些反应如何传播或减弱仍然未知。这项研究的目的是进一步确定Toll样受体（TLR）4和WNT1诱导信号通路蛋白1（WISP1）是否可能导致有害的机械通气，特别是研究巨噬细胞在呼吸机引起的肺损伤中的作用。设计了一项前瞻性，随机对照动物实验，雄性，野生型（WT）C57BL / 6小鼠，TLR4基因敲除（TLR4-/-）和lyzTLR4基因敲除（lyzTLR4-/-）小鼠衰老8〜12周被使用。麻醉动物并随机分为自发呼吸（SB）组或高潮气量（VT，20 ml / kg）机械通气（HTV）组。组织学评估 分析血浆和支气管肺泡灌洗液（BALF）浓度中伊文氏蓝白蛋白（EBA）的肺泡-毛细血管通透性，WISP1蛋白水平，巨噬细胞炎性蛋白2（MIP-2）和白介素6（IL-6）。HTV组与C57BL / 6小鼠的WISP1和EBA比例显着增加，WISP1蛋白水平显着降低，血浆IL-6，MIP-2显着降低以及促炎性细胞因子的BALF浓度有关在TLR4-/-和lyzTLR4-/-敲除小鼠中。在TLR4-/-小鼠和lyzTLR4-/-小鼠中，SB组和HTV组之间在H＆E得分，EBA比例和促炎细胞因子水平方面也存在显着差异。与靶向lyzTLR4的小鼠相比，整个靶向TLR4的小鼠可以进一步改善各种炎症变化和损伤。此外，TLR4-/-小鼠和lyzTLR4-/-小鼠对rWISP1和/或BMMC处理的反应不同。TLR4-/-小鼠对rWISP1无反应，而lyzTLR4-/-小鼠仍对两种治疗均表现出剧烈反应。巨噬细胞上的TLR4和WISP1，尤其是前者，可能在呼吸机诱发的肺损伤期间有助于促炎性细胞因子的释放。有害的机械通气可能导致类似于感染的免疫反应。