Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
Division of Respirology, Dept of Medicine, McMaster University and St Joseph's Healthcare, Hamilton, ON, Canada.
Eur Respir J. 2019 May 30;53(5). doi: 10.1183/13993003.01291-2018. Print 2019 May.
The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, , that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.
导致肺气肿的慢性气道疾病中的炎症反应尚未完全明确。我们假设肺嗜酸性粒细胞有助于在小鼠模型中扩大气腔，并有助于慢性阻塞性肺疾病（COPD）患者发生肺气肿。
使用慢性 2 型肺部炎症的转基因小鼠模型（I5/hE2）来研究导致气腔扩大的嗜酸性粒细胞依赖性机制。进行了转化研究，以检查慢性气道疾病患者的痰液中嗜酸性粒细胞和基质金属蛋白酶（MMP）-12 水平。
在 I5/hE2 小鼠中发现了气腔扩大，并且依赖于嗜酸性粒细胞。对 I5/hE2 支气管肺泡灌洗液的检查发现 MMP-12 升高，这是肺气肿的一种介质。我们表明，嗜酸性粒细胞衍生的白细胞介素（IL）-13 促进肺泡巨噬细胞 MMP-12 的产生。I5/hE2 小鼠的气腔扩大依赖于 MMP-12 和嗜酸性粒细胞衍生的 IL-4/13。与此一致，在痰液嗜酸性粒细胞增多和 CT 肺气肿证据的 COPD 患者中，MMP-12 升高，并且与 1 秒用力呼气量呈负相关。
慢性 2 型肺部炎症的小鼠模型表现出气腔扩大，依赖于 MMP-12 和嗜酸性粒细胞衍生的 IL-4/13。在慢性气道疾病患者中，肺嗜酸性粒细胞增多与 MMP-12 水平升高相关，MMP-12 是肺气肿的预测指标。这些发现表明，嗜酸性粒细胞有助于哮喘和 COPD 相关病理的一种被低估的机制。
