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

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, Robert G. Presson, Sanjay Sethi, Irina Petrache

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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 exsmoker 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.

Original languageEnglish (US)
Pages (from-to)2470-2479
Number of pages10
JournalJournal of Clinical Investigation
Volume121
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Clauss, M., Voswinckel, R., Rajashekhar, G., Sigua, N. L., Fehrenbach, H., Rush, N. I., Schweitzer, K. S., Yildirim, A. Ö., Kamocki, K., Fisher, A. J., Gu, Y., Safadi, B., Nikam, S., Hubbard, W. C., Tuder, R. M., Twigg, H. L., Presson, R. G., Sethi, S., & Petrache, I. (2011). Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice. Journal of Clinical Investigation, 121(6), 2470-2479. https://doi.org/10.1172/JCI43881