Doxycycline alleviates paraquat-induced acute lung injury by inhibiting neutrophil-derived matrix metalloproteinase 9
Doxycycline alleviates paraquat-induced acute lung injury by inhibiting neutrophil-derived matrix metalloproteinase 9
复制标题
多西环素通过抑制中性粒细胞衍生的基质金属蛋白酶 9 减轻百草枯诱导的急性肺损伤
DOI：
10.1016/j.intimp.2019.04.015
复制
发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Zhang, Jin-song
中科院分区：
文献类型：
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作者：
Zhang, Feng;Hu, Liang;Zhang, Jin-song
百草枯（PQ）是一种剧毒除草剂，在故意或意外中毒后，选择性地在肺中蓄积，并通过氧化和炎症过程引起肺损伤。由此产生的急性肺损伤（ALI）的特征是中性粒细胞浸润和广泛的炎症，并伴有快速呼吸衰竭。然而，缺乏有效的治疗方法。我们测试了抑制嗜中性粒细胞衍生的基质金属蛋白酶9（MMP 9）可以改善炎症环境和减轻PQ诱导的ALL的假设。通过测量肺静态顺应性、支气管肺泡灌洗液（BALF）和肺的细胞计数和中性粒细胞百分比、肺泡毛细血管通透性和组织病理学肺损伤评分来评估PQ气雾剂气管内注射的小鼠的肺损伤。通过明胶酶谱法评估MMP 9/2活性，并通过免疫荧光共染色评估中性粒细胞和MMP 9在肺中的位置。在中性粒细胞耗竭实验中，小鼠腹膜内接受抗Ly 6 G抗体;对于MMP抑制实验，通过管饲法施用MMP抑制剂多西环素（DOX）。在PQ诱导的ALI中，MMP 9而非MMP 2的活性显著增加。中性粒细胞耗竭减少炎症负荷，改善肺水肿，并减少PQ诱导的MMP 9过表达。一致地，DOX口服给药小鼠降低了由PQ激活的MMP 9的过表达，并表型模仿了中性粒细胞耗竭后观察到的PQ诱导的ALI的消退。总之，我们的研究结果首次表明，DOX是通过一种机制，涉及减少嗜酸性粒细胞衍生的MMP 9的活性参与PQ诱导的ALI的解决。我们推测DOX可能代表PQ诱导的ALI的一种新的治疗策略。
Paraquat (PQ), a highly toxic herbicide, selectively accumulates in the lungs and causes pulmonary damage through oxidative and inflammatory processes after intentional or accidental poisoning. The resulting acute lung injury (ALI) is characterized by neutrophil infiltration and extensive inflammation with rapid respiratory failure. However, effective therapies are lacking. We tested the hypothesis that suppressing neutrophil-derived matrix metalloproteinase 9 (MMP9) would ameliorate the inflammatory milieu and alleviate PQ-induced ALL Lung injury was assessed in mice intratracheally injected with PQ aerosol by measuring the lung static compliance, cell count and neutrophil percentage of the bronchoalveolar lavage fluid (BALF) and lung, alveolar-capillary permeability, and histopathological lung injury scores. MMP9/2 activity was assessed by gelatin zymography, and the location of neutrophils and MMP9 in the lung was evaluated by immunofluorescence costaining. In the neutrophil depletion experiment, mice received anti-Ly6G antibody intraperitoneally; for the MMP inhibition experiment, an MMP inhibitor, doxycycline (DOX), was administered by gavage. In PQ-induced ALI, the activity of neutrophil-derived MMP9 but not MMP2 increased significantly. Neutrophil depletion reduced the inflammatory burden, improved pulmonary edema, and reduced the PQ-induced overexpression of MMP9. Consistently, oral delivery of DOX to mice decreased the overexpression of MMP9 that was activated by PQ and phenocopied the resolution of PQ-induced ALI observed after neutrophil depletion. Taken together, our results show for the first time that DOX is involved in the resolution of PQ-induced ALI via a mechanism involving reducing the activity of neutrophil-derived MMP9. We speculate that DOX may represent a novel therapeutic strategy for PQ-induced ALI.