Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

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Abstract

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 EMAPII 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 EMAPII 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.

Authors

Matthias Clauss, Robert Voswinckel, Gangaraju Rajashekhar, Ninotchka L. Sigua, Heinz Fehrenbach, Natalia I. Rush, Kelly S. Schweitzer, Ali Ö. Yildirim, Krzysztof Kamocki, Amanda J. Fisher, Yuan Gu, Bilal Safadi, Sandeep Nikam, Walter C. Hubbard, Rubin M. Tuder, Homer L. Twigg III, Robert G. Presson, Sanjay Sethi, Irina Petrache