Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
Unidad de Cuidados Intensivos Cardiológicos, Área del Corazón, Hospital Universitario Central de Asturias, Oviedo, Spain.
Thorax. 2018 Apr;73(4):321-330. doi: 10.1136/thoraxjnl-2017-210105. Epub 2017 Sep 25.
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.
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).
Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ 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.
Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.
中性粒细胞在迁移过程中可能会通过释放细胞毒性分子导致组织破坏。然而，在肺损伤的实验模型中观察到的中性粒细胞耗竭的益处与中性粒细胞减少症患者的不良预后并不相符。
为了阐明中性粒细胞在修复过程中的作用，在发生呼吸机诱导的肺损伤（VILI）后，对小鼠进行中性粒细胞耗竭，并在自主呼吸 48 小时后进行研究。采集肺部组织，测量炎症介质和基质金属蛋白酶。收集接受机械通气的急性呼吸窘迫综合征患者的支气管肺泡灌洗液（BALF），无论是否存在中性粒细胞减少症，测量相同的介质，并在肺泡修复的体外模型中研究其作用。最后，在 VILI 后用外源性基质金属蛋白酶-9（MMP-9）对中性粒细胞减少症小鼠进行治疗。
中性粒细胞减少症动物的肺部显示出修复延迟，并表现出更高水平的肿瘤坏死因子-α、干扰素-γ 和巨噬细胞炎症蛋白 2，并且缺乏 MMP-9。接受机械通气的急性呼吸窘迫综合征中性粒细胞减少症患者的 BALF 显示出相似的结果。中性粒细胞减少症患者的 BALF 在体外产生的上皮伤口闭合率较慢，通过去除胶原蛋白或添加外源性 MMP-9 可改善这种情况。最后，在 VILI 后用外源性 MMP-9 治疗中性粒细胞减少症小鼠可减少组织损伤，而不改变细胞因子浓度。
中性粒细胞释放的 MMP-9 对于适当的基质处理和肺修复是必需的。
