Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9
Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9
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DOI：
10.1136/thoraxjnl-2017-210105
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发表时间：
2018-04-01
期刊：
影响因子：
10
通讯作者：
Albaiceta, Guillermo M.
中科院分区：
文献类型：
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作者：
Blazquez-Prieto, Jorge;Lopez-Alonso, Ines;Albaiceta, Guillermo M.
背景中性粒细胞在迁移过程中可通过释放细胞毒性分子引起组织破坏。然而，在肺损伤的实验模型中观察到的中性粒细胞耗竭的好处并不对应于血小板减少症patients.Methods的不良结果，以澄清中性粒细胞在修复过程中的作用，小鼠呼吸机诱导的肺损伤（VILI）的肺损伤后呈现血小板减少症，并随后为48小时的自主呼吸。收集肺，测量炎症介质和基质金属蛋白酶。收集急性呼吸窘迫综合征（伴或不伴中性粒细胞减少）通气患者的支气管肺泡灌洗液（BALF），测量相同的介质，并研究其在离体肺泡修复模型中的作用。最后，用外源性基质金属蛋白酶-9（MMP-9）治疗VILI后的肺功能衰竭小鼠。结果肺功能衰竭动物的肺表现出延迟修复，并显示较高水平的肿瘤坏死因子α，干扰素γ和巨噬细胞炎性蛋白2，和MMP-9的缺乏。急性呼吸窘迫综合征患者的BALF结果相似。从支气管肺泡灌洗液中获得了延迟关闭率上皮伤口离体，这是改善了去除胶原蛋白或添加外源性MMP-9。最后，用外源性MMP-9治疗后VILI减少组织损伤，而不改变细胞因子concentration.Conclusion释放MMP-9从中性粒细胞需要足够的基质处理和肺修复的血小板减少小鼠。
Background Neutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients.Methods To clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9).Results Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor alpha, interferon gamma and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations.Conclusion Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.