Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.

中文翻译：

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应激诱导的嗜酸性粒细胞活化导致肺切除术后术后并发症发生率和死亡率


胸外科手术后呼吸衰竭比腹部手术后更常见。尽管这种并发症的病因通常归因于接受胸外科手术的患者存在的潜在肺部疾病，但这种观点通常是没有根据的，因为许多术前肺功能正常的患者即使在肺组织最小切除后也经常需要长期供氧。使用肺切除术的小鼠模型和接受肺或腹部器官切除术的患者的外周血样本，我们证明肺部手术会启动促炎环，导致剩余肺组织损伤、非心源性肺水肿、缺氧，甚至死亡。具体来说，我们证明小鼠肺组织切除会增加稳态细胞因子白细胞介素 7 的浓度，从而导致 2 型先天淋巴细胞的局部和全身激活。这个过程激活了肺驻留嗜酸性粒细胞，并以粒细胞-巨噬细胞集落刺激因子依赖性方式促进了应激诱导的嗜酸性粒细胞在骨髓中成熟，导致小鼠和人类的系统性嗜酸性粒细胞增多症。肺驻留嗜酸性粒细胞中诱导型一氧化氮合酶的上调导致组织亚硝基化、肺水肿、缺氧，有时甚至导致死亡。在任何阶段破坏这种激活级联反应可改善小鼠模型中肺切除术后的有害结果并提高生存率。我们的数据表明，重新利用美国食品和药物管理局批准的嗜酸性粒细胞靶向策略可能会提供治疗干预，以改善因良性或恶性病因需要肺切除术的患者的预后。