Zhang Chaofeng, Hu Shanshan, Zosky Graeme R, Wei Xin, Shu Shuhua, Wang Di, Chai Xiaoqing
Department of Anesthesiology, First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
Shock. 2021 Feb 1;55(2):236-243. doi: 10.1097/SHK.0000000000001591.
Lung-recruited Ly6Chi monocytes had been shown to be involved in ventilator-induced lung injury (VILI). Our present study aimed to investigate whether the cyclooxygenase-2 (COX-2) inhibition modulates the function of lung-recruited Ly6Chi monocytes in a mouse model of VILI.
Mice were exposed to lipopolysaccharide (LPS; 20 ng) intraperitoneally prior to injurious mechanical ventilation (Vt = 30 mL/kg, PEEP = 0 cmH2O). A subgroup of mice was treated with intravenous parecoxib (30 mg/kg), a COX-2 inhibitor, 1 h prior to ventilation. Control mice received saline and were not ventilated. At the end of the experiment, blood gas analysis was performed and lung tissue was collected for histological assessment. Flow cytometry was employed to quantify the different populations of lung monocytes/macrophages and their function. Isolated Ly6Chi cells were used to measure the intracellular concentrations of reactive oxygen species (ROS) and nitric oxide (NO) by fluorescent probes, and cytokine production by cytometric bead array.
Exposure to LPS and injurious ventilation was associated with severe lung histological damage, oxygenation impairment, and pulmonary edema; all of which were largely attenuated following the treatment of parecoxib. Furthermore, flow cytometry analysis revealed that parecoxib caused a reduction in the number of the lung-recruited CD11bloLy6Chi monocytes while there was no effect on tissue-resident CD64+ alveolar macrophages. In addition, the production of oxidative stress products (ROS, NO), MHC-II expression, and inflammatory cytokines in response to LPS and VILI in CD11bloLy6Chi monocytes was ameliorated by parecoxib.
Parecoxib-induced alleviation of oxidative stress and inflammation in lung-recruited Ly6Chi monocytes may partly explain the beneficial action of COX-2 inhibition in VILI.
肺募集的Ly6Chi单核细胞已被证明参与呼吸机诱导的肺损伤（VILI）。我们目前的研究旨在调查环氧化酶-2（COX-2）抑制是否能调节VILI小鼠模型中肺募集的Ly6Chi单核细胞的功能。
在进行机械通气损伤（潮气量=30 mL/kg，呼气末正压=0 cmH2O）之前，小鼠腹腔内注射脂多糖（LPS；20 ng）。一组小鼠在通气前1小时静脉注射COX-2抑制剂帕瑞昔布（30 mg/kg）。对照小鼠接受生理盐水且不进行通气。实验结束时，进行血气分析并收集肺组织进行组织学评估。采用流式细胞术对肺单核细胞/巨噬细胞的不同群体及其功能进行定量分析。分离出的Ly6Chi细胞用于通过荧光探针测量细胞内活性氧（ROS）和一氧化氮（NO）的浓度，并通过细胞计数珠阵列检测细胞因子的产生。
暴露于LPS和机械通气损伤与严重的肺组织学损伤、氧合障碍和肺水肿相关；帕瑞昔布治疗后，所有这些情况均得到显著改善。此外，流式细胞术分析显示，帕瑞昔布使肺募集的CD11bloLy6Chi单核细胞数量减少，而对组织驻留的CD64+肺泡巨噬细胞没有影响。此外，帕瑞昔布改善了CD11bloLy6Chi单核细胞中氧化应激产物（ROS、NO）的产生、MHC-II表达以及对LPS和VILI的炎症细胞因子反应。
帕瑞昔布减轻肺募集的Ly6Chi单核细胞中的氧化应激和炎症，这可能部分解释了COX-2抑制在VILI中的有益作用。
