Abstract：
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear.
OBJECTIVE: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS.
METHODS: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry.
RESULTS: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher.
CONCLUSIONS: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.
OBJECTIVE: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS.
METHODS: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry.
RESULTS: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher.
CONCLUSIONS: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.
摘要：
背景：急性呼吸窘迫综合征（ARDS）是主要由败血症引起的肺部炎症过程。炎症的解决是涉及专门的促解决介质的内源性生物合成的活跃过程。包括分辨率D1（RvD1）。居民肺泡巨噬细胞（RAM）维持肺稳态，并在消退阶段发挥关键作用。然而,RAM在促进RvD1炎症消退中的作用尚不清楚.
目标：这里，我们研究了RvD1调节RAM促进ARDS消退的机制。
方法：通过雾化吸入给小鼠施用脂多糖和/或大肠杆菌，以建立自限ARDS模型。然后，RvD1在炎症反应高峰时施用。通过流式细胞术测量RAM的自我更新，通过双光子荧光成像测量RAM吞噬作用。此外,在第0-2,3-5和6-9天收集重症监护病房患者的血浆,使用三重四极杆/线性离子阱质谱法测量RvD1和S100A8/A9水平.
结果：研究发现RAM在ARDS期间缓解炎症中起关键作用，RvD1增强RAM增殖和吞噬作用，它被脂氧素A4受体(ALX，RvD1受体)抑制剂。用rS100A8/A9和/或S100A8/A9siRNA转染的原代RAM和S100A9-/-小鼠（也缺乏S100A8功能）均显示出更高的周转和吞噬功能，表明RvD1在分辨阶段通过抑制S100A8/A9的产生对RAM产生影响。RvD1在体内和体外降低S100A8/A9及其上游MAPK14水平。最后,在患者中，RvD1水平较低，但S100A8/A9水平更高。
结论：我们建议RvD1通过ALX/MAPK14/S100A8/A9信号通路改善RAM的自我更新和吞噬作用。血浆RvD1和S100A8/A9水平呈负相关,并与脓毒症诱导的ARDS的预后相关。
目标：这里，我们研究了RvD1调节RAM促进ARDS消退的机制。
方法：通过雾化吸入给小鼠施用脂多糖和/或大肠杆菌，以建立自限ARDS模型。然后，RvD1在炎症反应高峰时施用。通过流式细胞术测量RAM的自我更新，通过双光子荧光成像测量RAM吞噬作用。此外,在第0-2,3-5和6-9天收集重症监护病房患者的血浆,使用三重四极杆/线性离子阱质谱法测量RvD1和S100A8/A9水平.
结果：研究发现RAM在ARDS期间缓解炎症中起关键作用，RvD1增强RAM增殖和吞噬作用，它被脂氧素A4受体(ALX，RvD1受体)抑制剂。用rS100A8/A9和/或S100A8/A9siRNA转染的原代RAM和S100A9-/-小鼠（也缺乏S100A8功能）均显示出更高的周转和吞噬功能，表明RvD1在分辨阶段通过抑制S100A8/A9的产生对RAM产生影响。RvD1在体内和体外降低S100A8/A9及其上游MAPK14水平。最后,在患者中，RvD1水平较低，但S100A8/A9水平更高。
结论：我们建议RvD1通过ALX/MAPK14/S100A8/A9信号通路改善RAM的自我更新和吞噬作用。血浆RvD1和S100A8/A9水平呈负相关,并与脓毒症诱导的ARDS的预后相关。
