1 Department of Medicine.
Am J Respir Cell Mol Biol. 2014 Jun;50(6):1107-17. doi: 10.1165/rcmb.2013-0163OC.
The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.
急性呼吸窘迫综合征（ARDS）是一种严重的肺部疾病，目前尚无治愈方法，它会因支持生命的机械通气而加重，这种通气会通过呼吸机引起的肺损伤综合征加重肺水肿和炎症。最近，肺泡巨噬细胞上的膜离子通道瞬时受体电位香草酸 4（TRPV4）被证明可以介导高压力机械通气引起的小鼠肺血管通透性。本研究的目的是确定吸入含有 TRPV4 抑制剂钌红（RR）的纳米颗粒（NPs）是否可以预防小鼠呼吸机诱导的肺水肿。体外评估了含有 RR 的聚乳酸-羟基乙酸共聚物 NPs 阻断肺泡巨噬细胞和毛细血管内皮细胞中 TRPV4 介导的钙信号的能力。然后，用雾化 NPs 处理的成年 C57BL6 小鼠的肺在离体通气灌注实验中用于评估 NPs 预防高压机械通气引起的肺水肿的能力。聚乳酸-羟基乙酸共聚物 NPs（300nm）在体外释放 RR 长达 150 小时，并且在吞噬后长达 7 天内阻断细胞中 TRPV4 介导的钙信号。吸入的 NPs 在自主呼吸的小鼠肺泡中迅速被肺泡巨噬细胞吞噬，并在离体通气灌注实验中阻止了高压机械通气引起的血管通透性增加长达 72 小时。这些数据提供了一个原理证明，即吸入含有 TRPV4 抑制剂的 NPs 可预防呼吸机损伤数天，并暗示这种新型药物输送策略可用于在开始机械通气之前针对有呼吸机引起的肺损伤风险的患者的肺泡巨噬细胞。
