Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The First Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Surg Res. 2020 Dec;256:584-594. doi: 10.1016/j.jss.2020.06.062. Epub 2020 Aug 14.
Acute lung injury (ALI), manifested by progressive hypoxemia and respiratory distress, is associated with high morbidity and mortality, which lacks the effective therapies in clinics. Our previous studies demonstrated that maresin1 (MaR1), a specialized proresolving mediator, could effectively mitigate the inflammation of lipopolysaccharide (LPS)-induced ALI. However, whether MaR1 impacts the macrophage polarization to alleviate ALI remains unclear. Our study explored the effects and underlying mechanisms of MaR1 on the macrophage phenotypes in ALI.
Male BALB/c mice were subjected to endotracheal instillation of LPS to induce ALI and then intravenously injected with MaR1 or normal saline. Intraperitoneal administration of peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibitor GW9662 was given 30 mins before MaR1. We measured the pathohistologic changes, pulmonary edema, inflammatory cytokines, and the flow cytometry of macrophage phenotypes.
Our results illustrated that MaR1 ameliorated lung injury and increased monocyte or macrophage recruitment and the release of anti-inflammatory cytokines. The flow cytometry showed that MaR1 promoted polarization of CD11cCD206 (M2) macrophages and inhibited polarization of CD11cCD206 (M1) macrophages. Besides, the western blotting revealed that MaR1 increased the expression of PPAR-γ. The pretreatment with PPAR-γ antagonist GW9662 could significantly suppress the polarization of M2 macrophages and antagonize the protective effects of MaR1 on LPS-stimulated ALI.
MaR1 was able to promote M2 macrophage polarization by reversing LPS-mediated PPAR-γ inhibition, thereby expediting the recovery of LPS-stimulated ALI.
急性肺损伤（ALI）表现为进行性低氧血症和呼吸窘迫，发病率和死亡率高，临床上缺乏有效的治疗方法。我们之前的研究表明maresin1（MaR1），一种特殊的促解决介质，可以有效减轻脂多糖（LPS）诱导的 ALI 炎症。然而，MaR1 是否影响巨噬细胞极化以减轻 ALI 尚不清楚。我们的研究探讨了 MaR1 对 ALI 中巨噬细胞表型的影响及其潜在机制。
雄性 BALB/c 小鼠经气管内滴注 LPS 诱导 ALI，然后静脉注射 MaR1 或生理盐水。MaR1 给药前 30 分钟给予过氧化物酶体增殖物激活受体-γ（PPAR-γ）抑制剂 GW9662 腹腔内给药。我们测量了组织病理学变化、肺水肿、炎症细胞因子和巨噬细胞表型的流式细胞术。
我们的结果表明，MaR1 改善了肺损伤，增加了单核细胞或巨噬细胞的募集和抗炎细胞因子的释放。流式细胞术显示 MaR1 促进了 CD11cCD206（M2）巨噬细胞的极化，并抑制了 CD11cCD206（M1）巨噬细胞的极化。此外，Western blot 显示 MaR1 增加了 PPAR-γ 的表达。PPAR-γ 拮抗剂 GW9662 的预处理可显著抑制 M2 巨噬细胞的极化，并拮抗 MaR1 对 LPS 刺激的 ALI 的保护作用。
MaR1 能够通过逆转 LPS 介导的 PPAR-γ 抑制促进 M2 巨噬细胞极化，从而加速 LPS 刺激的 ALI 的恢复。
