Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (a.k.a. efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 ml/kg)) for 4 h. On day 1 after mechanical ventilation, Tlr4^+/+ or Tlr4^-/- bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4^+/+ BMDMs. Importantly, these pro-resolving effects by Tlr4^+/+ BMDMs were abolished in mice receiving Tlr4^-/- BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4^-/- BMDMs than that in those receiving Tlr4^+/+ BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4^+/+ BMDMs, but not Tlr4^-/- BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis.

中文翻译：

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在解决呼吸机引起的肺损伤期间，巨噬细胞胞吞作用需要 TLR4

机械通气是呼吸衰竭患者的一种维持生命的疗法，但会导致进一步的肺损伤，称为呼吸机诱发的肺损伤 (VILI)。然而，VILI 恢复的内在分子机制仍然未知。凋亡细胞的吞噬作用（又名胞吞作用）是协调炎症成功消退的关键机制。在这里，我们展示了巨噬细胞 Toll 样受体 (TLR) 4 在胞吞作用和 VILI 分辨率中的正调控。小鼠耗尽肺泡巨噬细胞，然后进行有害通气（潮气量，20 毫升/千克））4 小时。机械通气后第 1 天，Tlr4 ^+/+或 Tlr4 ^-/-骨髓来源的巨噬细胞 (BMDM) 被气管内施用给肺泡巨噬细胞耗竭的小鼠。我们观察到肺泡巨噬细胞耗竭的小鼠在通气后表现出中性粒细胞炎症、渗出蛋白、肺水肿和肺组织损伤的有缺陷的消退，而这些延迟的反应通过施用 Tlr4 ^+/+ BMDMs 逆转。重要的是，Tlr4 ^+/+ BMDMs 的这些促分辨作用在接受 Tlr4 ^-/- BMDMs 的小鼠中被消除。与接受 Tlr4 ^{+/+ 的}小鼠相比，接受 Tlr4 ^-/- BMDMs 的小鼠的支气管肺泡灌洗液中含有凋亡细胞或体的巨噬细胞数量要少得多BMDM。巨噬细胞 TLR4 缺失促进了去整合素和金属蛋白酶 17 的成熟，并增强了机械通气时的 Mer 裂解。热休克蛋白 70 显着增加了 Mer 酪氨酸激酶表面表达、凋亡中性粒细胞的吞噬作用，并挽救了接受 Tlr4 ^+/+ BMDM 而不是 Tlr4 ^-/- BMDM 的肺泡巨噬细胞耗竭小鼠的炎症表型。我们的结果表明巨噬细胞 TLR4 通过调节 Mer 介导的胞吞作用促进 VILI 的消退。