Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice
Matthias Clauss, … , Sanjay Sethi, Irina Petrache
Matthias Clauss, … , Sanjay Sethi, Irina Petrache
Published May 16, 2011
Citation Information: J Clin Invest. 2011;121(6):2470-2479. https://doi.org/10.1172/JCI43881.
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Research Article Pulmonology

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

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

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Figure 4

Increased EMAPII in human COPD.

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Increased EMAPII in human COPD. (A) Secreted EMAPII in the acellular BAL...
(A) Secreted EMAPII in the acellular BALF from otherwise healthy active smokers (triangles; n = 9) compared with that from nonsmokers (circles; n = 10). Mean arbitrary units measured by densitometry were normalized by protein concentration (AU/μg/ml; mean ± SD, *P = < 0.01, t test). (B) Box plot of secreted mature EMAPII in acellular BALF from healthy nonsmokers, ex-smokers without COPD, or ex-smokers with COPD shown in arbitrary units normalized by vinculin densitometry units (*P < 0.05, ANOVA; n = 15/group). Demographic and clinical data are shown in Supplemental Table 1. (C) EMAPII detection by immunostaining with polyclonal EMAPII antibody (red, arrows; DAPI-nuclei are stained in blue) in lung parenchyma of patients with emphysema (bottom panels) compared with subjects without lung disease (normal lung, top panel). Note intense EMAPII staining in the alveolar wall (alv; inset) in emphysematous lungs. IF, immunofluorescence. Scale bar: 50 μm. (D) Box plot of lung EMAPII expression in lung sections from subjects without lung disease (normal; n = 4), with emphysema (emphys; n = 9), or with usual interstitial pneumonitis (UIP; n = 13) (immunohistochemistry staining arbitrary units; *P < 0.05 versus normal, ANOVA). (B and D) Lines within the boxes show medians; bounds of the boxes show 25th and the 75th percentiles of the data, respectively; and whiskers show outliers (5th and 95th percentiles, respectively).