Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvβ5 integrin pathway in TLR4-mediated inflammation and injury.
Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvβ5 integrin pathway in TLR4-mediated inflammation and injury.
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机械通气增强肺外脓毒症引起的肺损伤：WISP1-αvβ5整合素通路在TLR4介导的炎症和损伤中的作用
DOI：
10.1186/s13054-018-2237-0
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发表时间：
2018-11-16
期刊：
影响因子：
--
通讯作者：
Zhang LM
中科院分区：
文献类型：
--
作者：
Ding X;Tong Y;Jin S;Chen Z;Li T;Billiar TR;Pitt BR;Li Q;Zhang LM
健康肺的大潮气量通气或更适度的机械通气（MTV）加重现有的急性肺损伤（ALI）会产生呼吸机诱导的肺损伤。肺外脓毒症是否使肺对MTV敏感尚不清楚。我们采用盲肠结扎穿孔（CLP），12小时后给予MTV的两次打击模型（10 ml/kg; 6 h）通过对比野生型和TLR 4 −/−小鼠的以下方面来确定非损伤性MTV是否增强CLP诱导的ALI：肺泡-毛细血管通透性、组织病理学和肺内WNT诱导分泌蛋白1（WISP 1）和整合素β5水平;血浆细胞因子和趋化因子（TNF-α、IL-6、MIP-2、MCP-1）水平和肺内中性粒细胞浸润;以及通过肺内激活JNK、p38和ERK的其他炎症信号传导。用针对WISP 1、整联蛋白β5或IgG的体内中和抗体预处理单独的小鼠队列作为对照，并在两次打击模型中重复呈现的表型分型;在这前三次实验中每组有10只小鼠。此外，从野生型和TLR 4 −/−、MyD 88 −/−和TRIF−/−小鼠中分离的腹膜巨噬细胞（PM）用于鉴定WISP 1-TLR 4-整联蛋白β5通路;并通过siRNA处理检查了整联蛋白β5在LPS引发的PM中WISP 1诱导的细胞因子和趋化因子产生中的必要作用。MTV本身不会引起ALI，但会加剧先前接受CLP的小鼠的肺泡毛细血管通透性、组织病理学评分和肺部炎症指数的增加;这种两次打击模型的作用在TLR 4 −/−小鼠中被消除。伴随这些发现的是两次打击模型中肺内WISP 1和整合素β5的显著增加。抗WISP 1或抗整联蛋白β5抗体部分抑制两次打击表型。在PM中，TLR 4激活导致整合素β5表达增加，这是MyD 88和NF-κB依赖的。重组WISP 1增加了PM中LPS诱导的细胞因子释放，该释放可通过沉默TLR 4或整合素β5来抑制。这些数据首次表明，非损伤性机械通气可加重肺外脓毒症引起的ALI，强调了重症监护中常见事件（脓毒症和机械通气）的潜在相互作用，并且WISP 1-TLR 4-整合素β5通路促成了这一现象。本文的在线版本（10.1186/s13054-018-2237-0）包含补充材料，可供授权用户使用。
High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV. We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4−/− mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin β5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK. A separate cohort of mice was pretreated with intratracheal neutralizing antibodies to WISP1, integrin β5 or IgG as control and the presented phenotyping repeated in a two-hit model; there were 10 mice per group in these first three experiments. Also, isolated peritoneal macrophages (PM) from wildtype and TLR4−/−, MyD88−/− and TRIF−/− mice were used to identify a WISP1–TLR4–integrin β5 pathway; and the requisite role of integrin β5 in WISP1-induced cytokine and chemokine production in LPS-primed PM was examined by siRNA treatment. MTV, that in itself did not cause ALI, exacerbated increases in alveolar-capillary permeability, histopathologic scoring and indices of pulmonary inflammation in mice that previously underwent CLP; the effects of this two-hit model were abrogated in TLR4−/− mice. Attendant with these findings was a significant increase in intrapulmonary WISP1 and integrin β5 in the two-hit model. Anti-WISP1 or anti-integrin β5 antibodies partially inhibited the two-hit phenotype. In PM, activation of TLR4 led to an increase in integrin β5 expression that was MyD88 and NF-κB dependent. Recombinant WISP1 increased LPS-induced cytokine release in PM that was inhibited by silencing either TLR4 or integrin β5. These data show for the first time that otherwise noninjurious mechanical ventilation can exacerbate ALI due to extrapulmonary sepsis underscoring a potential interactive contribution of common events (sepsis and mechanical ventilation) in critical care, and that a WISP1–TLR4–integrin β5 pathway contributes to this phenomenon. The online version of this article (10.1186/s13054-018-2237-0) contains supplementary material, which is available to authorized users.
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