Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.
JCI Insight. 2022 Feb 8;7(3):e149870. doi: 10.1172/jci.insight.149870.
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8-/- mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
急性呼吸窘迫综合征（ARDS）导致灾难性的肺衰竭，迫切需要改进早期识别和治疗方法。中性粒细胞浸润是 ARDS 的一个标志，与组织破坏性免疫效应物的释放有关，如基质金属蛋白酶（MMPs）和膜锚定金属蛋白酶解整合素（ADAMs）。在这里，我们通过活体显微镜观察到 Adam8-/-小鼠的中性粒细胞迁移受损。在小鼠肺炎模型中，ADAM8 的基因缺失和药理学抑制均减弱了中性粒细胞浸润和肺损伤，同时改善了细菌的控制。出乎意料的是，中性粒细胞功能的改变不是由于蛋白酶解作用受损，而是由于 ADAM8 与肌球蛋白 1f 之间的细胞内相互作用减少，从而抑制了中性粒细胞的运动。在 2 个 ARDS 队列中，我们分析了肺液蛋白水解特征，并确定 ADAM8 活性与疾病严重程度呈正相关。我们提出，在肺炎和 ARDS 等急性炎症性肺疾病中，ADAM8 抑制可能允许微调中性粒细胞反应以获得治疗效果。
