Abstract：
Angiotensin II (Ang II) is associated with macrophage polarization and apoptosis, but the role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. However, the effect of AT2Rs on alveolar macrophages and mechanical ventilation-induced lung injury has not been determined. Mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats and LPS-stimulated rat alveolar macrophages (NR8383) were used to determine the effects of AT2Rs, selective AT2R agonists and selective AT1Rs or AT2R antagonists. Macrophage polarization, apoptosis, and related signaling pathways were assessed via western blotting, QPCR and flow cytometry. AT2R expression was decreased in LPS-stimulated rat alveolar macrophages (NR8383). Administration of the AT2R agonist CGP-42112 was associated with an increase in AT2R expression and M2 polarization, but no effect was observed upon administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan. In mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats, the administration of the AT2R agonist C21 was associated with attenuation of the pathological damage score, lung wet/dry weight, cell count and protein content in BALF. C21 can significantly reduce proinflammatory factor TNF-α, IL-1β levels, increase anti-inflammatory factor IL-4, IL-10 levels in BALF, compared with the model group (p < 0.01). Similarly, compared with those at the same time points, the M1/M2 ratios in alveolar macrophages and apoptosis in peritoneal macrophages at 4 h, 6 h and 8 h in the mechanical ventilation models were lower after C21 administration. These findings indicated that the expression of AT2Rs in alveolar macrophages mediates M1 macrophage polarization and apoptosis and that AT2Rs play a protective role in mediating mechanical ventilation-induced lung injury.
摘要：
血管紧张素II（AngII）与巨噬细胞极化和凋亡有关，但是血管紧张素2型受体（AT2R）在这些过程中的作用仍存在争议。然而,AT2R对肺泡巨噬细胞和机械通气诱导的肺损伤的影响尚未确定.机械通气引起的Sprague-Dawley（SD）大鼠肺损伤和LPS刺激的大鼠肺泡巨噬细胞（NR8383）用于确定AT2R的影响，选择性AT2R激动剂和选择性AT1R或AT2R拮抗剂。巨噬细胞极化，凋亡，和相关的信号通路通过蛋白质印迹进行评估，QPCR和流式细胞术。在LPS刺激的大鼠肺泡巨噬细胞(NR8383)中AT2R表达降低。AT2R激动剂CGP-42112的给药与AT2R表达和M2极化的增加有关，但AT2R拮抗剂PD123319或AT1R拮抗剂缬沙坦给药后未观察到效果。在机械通气诱导的Sprague-Dawley（SD）大鼠肺损伤中，AT2R激动剂C21的给药与病理损伤评分的减弱有关，肺湿/干重，BALF中的细胞计数和蛋白质含量。C21可显著降低促炎因子TNF-α,IL-1β水平,增加BALF中抗炎因子IL-4，IL-10的水平，与模型组比较(p<0.01)。同样，与同一时间点相比，4h时肺泡巨噬细胞M1/M2比值和腹膜巨噬细胞凋亡，机械通气模型中的6h和8h在C21给药后较低。这些发现表明，肺泡巨噬细胞中AT2R的表达介导M1巨噬细胞极化和凋亡，并且AT2R在介导机械通气引起的肺损伤中起保护作用。
