Resolvin D1 Reduces Lung Infection and Inflammation Activating Resolution in Cystic Fibrosis
Resolvin D1 Reduces Lung Infection and Inflammation Activating Resolution in Cystic Fibrosis
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DOI：
10.3389/fimmu.2020.00581
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发表时间：
2020-04-28
影响因子：
7.3
通讯作者：
Recchiuti, Antonio
中科院分区：
文献类型：
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作者：
Isopi, Elisa;Mattoscio, Domenico;Recchiuti, Antonio
未消退的肺部炎症和铜绿假单胞菌感染是囊性纤维化（CF）发病率和死亡率的根本原因。内源性脂质介质消退素（Rv）D1是一种有效的调节剂的决议，其作用，行动和治疗潜力CF的兴趣。在这里，我们研究了RvD 1在囊性纤维化临床前模型中的作用和疗效。用RvD 1治疗慢性铜绿假单胞菌肺部感染的Cftr敲除小鼠，以评估肺细菌负荷、炎症和组织损伤的差异。在用铜绿假单胞菌离体感染期间，用RvD 1处理来自患有CF的志愿者的细胞，并测定对吞噬作用和炎症信号传导的影响。在CF小鼠中，RvD 1减少了细菌负荷、中性粒细胞浸润和肺病理学的组织学体征，改善了疾病的临床评分。从机制上讲，RvD 1增加了体内巨噬细胞介导的细菌和白细胞清除。这些发现的临床意义得到了CF志愿者的原代白细胞和上皮细胞的作用的支持，其中RvD 1增强了铜绿假单胞菌的吞噬作用，并减少了与NF-κ B活化和白细胞浸润相关的基因和蛋白质。CF患者痰液中RvD 1的浓度与CF肺病理中涉及的细胞因子和趋化因子的浓度也呈负相关。这些发现证明了RvD 1在增强肺部炎症和感染消退方面的功效，并为其作为CF原型新型促消退治疗方法的潜力提供了概念证明。
Non-resolving lung inflammation and Pseudomonas aeruginosa infections are the underlying cause of morbidity and mortality in cystic fibrosis (CF). The endogenous lipid mediator resolvin (Rv) D1 is a potent regulator of resolution, and its roles, actions, and therapeutic potential in CF are of interest. Here, we investigated actions and efficacy of RvD1 in preclinical models of cystic fibrosis. Cftr knockout mice with chronic P. aeruginosa lung infection were treated with RvD1 to assess differences in lung bacterial load, inflammation, and tissue damage. Cells from volunteers with CF were treated with RvD1 during ex vivo infection with P. aeruginosa, and effects on phagocytosis and inflammatory signaling were determined. In CF mice, RvD1 reduced bacterial burden, neutrophil infiltration, and histological signs of lung pathology, improving clinical scores of diseases. Mechanistically, RvD1 increased macrophage-mediated bacterial and leukocyte clearance in vivo. The clinical significance of these findings is supported by actions in primary leukocytes and epithelial cells from volunteers with CF where RvD1 enhanced P. aeruginosa phagocytosis and reduced genes and proteins associated to NF-kappa B activation and leukocyte infiltration. Concentration of RvD1 in sputum from patients with CF was also inversely correlated to those of cytokines and chemokines involved in CF lung pathology. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung inflammation and infections and provide proof of concept for its potential as a prototypic novel pro-resolutive therapeutic approach for CF.