Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice
Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice
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DOI：
10.1172/jci43881
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
--
作者：
Clauss, Matthias;Voswinckel, Robert;Petrache, Irina
肺气肿是一种以肺泡细胞损失和炎症为特征的疾病。近年来，肺泡结构细胞的过度凋亡已成为肺气肿发生发展的主要机制。在这里，我们研究了促凋亡和单核细胞趋化因子内皮单核细胞激活蛋白2（EMAPII）。与对照转基因小鼠相比，EMAPII在小鼠中的肺特异性过表达导致肺泡结构简化、细胞凋亡和巨噬细胞积聚。此外，在香烟烟雾诱导的（CS诱导的）肺气肿的小鼠模型中，EMAPII水平在鼠肺中显著增加。这种上调是肺气肿发展所必需的，因为EMAPH的中和抗体导致肺泡细胞凋亡、炎症和肺气肿相关的肺泡和小气道结构变化减少，并改善肺功能。EMAPII上调的机制涉及一个肺水肿依赖性前馈回路，因为在肺中滴注半胱天冬酶-3显著增加EMAPH表达，而半胱天冬酶抑制剂降低其产生，即使在转基因EMAPII小鼠中。这些发现可能具有临床意义，因为与非吸烟者相比，当前吸烟者和既往吸烟者慢性阻塞性肺疾病（COPD）患者的支气管肺泡灌洗液中分泌的EMAPII水平增加。总之，我们认为，EMAPII延续机制的CS诱导的肺气肿小鼠，鉴于其分泌的性质，是一个合适的目标，中和抗体治疗。
Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPH resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPH expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and ex-smoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.