Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China; Department of Anesthesiology, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China.
Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):112832. doi: 10.1016/j.intimp.2024.112832. Epub 2024 Oct 2.
The lungs are highly susceptible to damage during sepsis, with severe lung injury potentially progressing to acute respiratory distress syndrome and even fatal sepsis. Effective efferocytosis of apoptotic cells is crucial in alleviating inflammation and tissue injury.
We established a septic lung injury mouse model via intraperitoneal injection of lipopolysaccharide. Lung injury was assessed by histology, immunofluorescence, neutrophil immunohistochemistry staining, and cytokine detection. We extracted alveolar macrophages by bronchoalveolar lavage and primary macrophages from mouse bone marrow to investigate the regulatory effects of Dexmedetomidine (DEX) on efferocytosis. We further validated the molecular mechanisms underlying the regulation of macrophage efferocytosis by DEX through knockdown of AXL expression. Additionally, we examined the efferocytic ability of monocytes isolated from patients.
We discovered that DEX treatment effectively alleviated pulmonary injury and inflammation. Lipopolysaccharide reduced macrophage efferocytosis and AXL expression which were reversed by DEX. We also found DEX inhibited the increased activation of A Disintegrin And Metalloproteinase 10 (ADAM10) and the production of soluble AXL. Moreover, our findings demonstrated that DEX decreased the elevated ROS production linked to higher ADAM10 activation. Blocking AXL negated DEX's benefits on efferocytosis and lung protection. Efferocytosis in monocytes from septic lung injury patients was notably lower than in healthy individuals.
Our findings demonstrated that DEX treatment effectively reduces septic lung injury by promoting macrophage efferocytosis through ROS/ADAM10/AXL signaling pathwway.
肺部在脓毒症中极易受损，严重的肺损伤可能进展为急性呼吸窘迫综合征，甚至致命的脓毒症。有效的细胞凋亡清除对于缓解炎症和组织损伤至关重要。
我们通过腹腔注射脂多糖建立了脓毒症肺损伤小鼠模型。通过组织学、免疫荧光、中性粒细胞免疫组化染色和细胞因子检测评估肺损伤。我们通过支气管肺泡灌洗提取肺泡巨噬细胞，并从鼠骨髓中提取原代巨噬细胞，以研究地塞米松（DEX）对吞噬作用的调节作用。我们进一步通过敲低 AXL 表达验证了 DEX 调节巨噬细胞吞噬作用的分子机制。此外，我们还检查了从患者中分离的单核细胞的吞噬能力。
我们发现 DEX 治疗可有效缓解肺损伤和炎症。脂多糖降低了巨噬细胞的吞噬作用和 AXL 表达，DEX 可逆转这种作用。我们还发现 DEX 抑制了 ADAM10 的过度激活和可溶性 AXL 的产生。此外，我们的研究结果表明，DEX 降低了与更高 ADAM10 激活相关的 ROS 产生的增加。阻断 AXL 消除了 DEX 对吞噬作用和肺保护的益处。脓毒症肺损伤患者的单核细胞吞噬作用明显低于健康个体。
我们的研究结果表明，DEX 通过 ROS/ADAM10/AXL 信号通路促进巨噬细胞吞噬作用，从而有效减轻脓毒症肺损伤。
