Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema
Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema
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DOI：
10.1172/jci10458
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发表时间：
2000-11-01
影响因子：
15.9
通讯作者：
Elias, JA
中科院分区：
文献类型：
--
作者：
Zheng, T;Zhu, Z;Elias, JA
吸烟是慢性阻塞性肺疾病（COPD）的主要病因。然而，只有少数吸烟者发展为显著的COPD，并且患有哮喘或哮喘样气道高反应性或嗜酸性粒细胞增多症的患者在香烟烟雾暴露后经历肺功能的加速丧失。肺部炎症是COPD患者肺部的特征性特征。令人惊讶的是，这种炎症的介质及其对COPD发病机制和各种自然史的贡献尚未明确。在这里，我们表明，IL-13，一个关键的细胞因子在哮喘，导致肺气肿与增强肺容量和顺应性，粘液化生，炎症，诱导过度表达时，在成年小鼠肺。MMP-2、MMP-9、MMP-12、MMP-13和MMP-14以及组织蛋白酶B、S、L、H和K在这种情况下由IL-13诱导。锌的添加，MMP或半胱氨酸蛋白酶拮抗剂治疗显着减少肺气肿和炎症，但不是在这些动物的粘液。这些研究表明，IL-13是肺中MMP和基于组织蛋白酶的蛋白水解途径的有效刺激剂。他们还证明IL-13通过MMP和组织蛋白酶依赖性机制引起肺气肿，并强调了可能是COPD和哮喘基础的常见机制。
Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. Zn addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.