Eosinophil-derived IL-13 promotes emphysema
Eosinophil-derived IL-13 promotes emphysema
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DOI：
10.1183/13993003.01291-2018
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发表时间：
2019-05-01
影响因子：
24.3
通讯作者：
Jacobsen, Elizabeth A.
中科院分区：
文献类型：
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作者：
Doyle, Alfred D.;Mukherjee, Manali;Jacobsen, Elizabeth A.
导致肺气肿的慢性气道疾病的炎症反应尚未完全确定。我们假设肺嗜酸性粒细胞增多会导致小鼠模型中的气腔扩大以及慢性阻塞性肺病（COPD）患者的肺气肿。使用慢性 2 型肺部炎症 (I5/hE2) 转基因小鼠模型来检查导致空腔扩大的嗜酸性粒细胞依赖性机制。收集人痰样本用于转化研究，检查慢性气道疾病患者的嗜酸粒细胞增多症和基质金属蛋白酶 (MMP)-12 水平。在 I5/hE2 小鼠中发现了空腔扩大，并且取决于嗜酸性粒细胞。 I5/hE2 支气管肺泡灌洗液检查发现 MMP-12（肺气肿的介质）升高。我们在体外证明，嗜酸性粒细胞衍生的白细胞介素 (IL)-13 可以促进肺泡巨噬细胞 MMP-12 的产生。 I5/hE2 小鼠的空腔扩大依赖于 MMP-12 和嗜酸性粒细胞衍生的 IL-4/13。与此一致的是，在痰液嗜酸性粒细胞增多和计算机断层扫描证据显示肺气肿的患者中，MMP-12 升高，并且与 1 秒用力呼气量呈负相关。慢性 2 型肺部炎症小鼠模型表现出依赖于 MMP-12 和嗜酸性粒细胞衍生的 IL-4/13 的空腔扩大。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，而 MMP-12 水平是肺气肿的预测因子。这些发现表明嗜酸性粒细胞导致哮喘和慢性阻塞性肺病相关病理的机制未被充分认识。
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, in vitro, 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.