Depletion of circulating monocytes suppresses IL-17 and HMGB1 expression in mice with LPS-induced acute lung injury
Depletion of circulating monocytes suppresses IL-17 and HMGB1 expression in mice with LPS-induced acute lung injury
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循环单核细胞的消耗抑制 LPS 诱导的急性肺损伤小鼠中 IL-17 和 HMGB1 的表达
DOI：
10.1152/ajplung.00389.2016
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发表时间：
2017-02-01
影响因子：
4.9
通讯作者：
Zhu, Lei
中科院分区：
文献类型：
--
作者：
Jiang, Zhilong;Zhou, Qianlin;Zhu, Lei
急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是危重症患者死亡的重要原因。巨噬细胞在ALI/ARDS的发病机制中发挥着重要作用。为探究循环单核细胞和肺泡常驻巨噬细胞（AMs）在ALI/ARDS中的作用及潜在机制，我们在脂多糖（LPS）诱导的ALI/ARDS小鼠模型中，通过使用氯膦酸盐脂质体（CL）耗竭循环单核细胞和AMs。我们的研究结果表明，在气管内给予LPS处理前2天静脉注射CL以耗竭循环单核细胞，可显著抑制ALI/ARDS小鼠的急性肺损伤，同时气管内给予LPS处理2天的小鼠肺部中性粒细胞浸润、白细胞介素-17、单核细胞趋化蛋白1、高迁移率族蛋白B1、细胞因子信号转导抑制因子3以及表面活性蛋白D（SP-D）均显著减少。相反，通过气管内给予CL耗竭AMs会加剧急性肺损伤，同时上述介质表达上调。通过腹腔注射抗小鼠CCL2中和抗体阻断单核细胞趋化蛋白1信号通路，可显著减轻急性肺损伤和中性粒细胞浸润。此外，AMs释放的介质可上调SP-D，因为用LPS处理小鼠的支气管肺泡灌洗液或LPS处理的RAW 264.7细胞的条件培养基处理原代小鼠II型肺泡上皮细胞后，这些细胞表达更多的SP-D。研究结果表明，在ALI/ARDS早期，循环单核细胞具有促炎作用，而AMs具有抗炎功能。本研究为通过调节循环单核细胞和AMs来治疗ALI/ARDS提供了分子基础。
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an important cause of mortality in critically ill patients. Macrophages play an important role in the pathogenesis of ALI/ARDS. To investigate the role and underlying mechanisms of circulating monocytes and resident alveolar macrophages (AMs) in ALI/ARDS, we depleted circulating monocytes and AMs by clodronate-loaded liposome ( CL) in a lipopolysaccharide (LPS)-induced ALI/ARDS mouse model. Our results indicated that depletion of circulating monocytes by intravenous injection of CL 2 days before intratracheal LPS treatment significantly suppressed the acute lung injury in mice with ALI/ARDS, accompanied with significant reduction in neutrophil influx, interleukin-17, monocyte chemoattractant protein 1, high-mobility group box 1 protein, suppressor of cytokine signaling 3, and surfactant protein D(SP-D) in the lungs of 2 days intratracheal LPS-treatedmice. In contrast, depletion of AMs by intratracheal delivery of CL enhanced the acute lung injury in association with upregulation of these mediators. Blocking monocyte chemoattractant protein 1 signaling by intraperitoneal instillation of anti-mouse CCL2 neutralizing antibody significantly reduced acute lung injury and neutrophil influx. In addition, SP-D was upregulated by mediators released from AMs because primary murine type II alveolar epithelial cells expressed more SP-D after treatment with bronchoalveolar lavage from LPS-treated mice or the conditioned media from LPS-treated RAW 264.7 cells. The results indicated that circulating monocytes are proinflammatory, but AMs have anti- inflammatory functions in the early phase of ALI/ARDS. The study provided a molecular basis for the treatment of ALI/ ARDS through modulation of circulating monocytes and AMs.