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 2

EMAPII is an essential mediator of CS-induced emphysema in mice.

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EMAPII is an essential mediator of CS-induced emphysema in mice. (A and ...
(A and B) EMAPII expression after CS exposure. (A) Production of EMAPII (pro and mature forms) in lung lysates in mice exposed to CS (4 weeks) compared with that in control mice exposed to ambient air (air control [AC]), assessed by Western blot (mean densitometry units [DUs] normalized to vinculin ± SEM; *P < 0.05 versus control; n = 5/group). (B) EMAPII localization in the lung parenchyma detected by coimmunofluorescence with EMAPII antiserum (green), CD11b antibody (red), and DAPI (blue). In controls, EMAPII expression is sparse, and EMAPII colocalized with macrophages (arrowheads) (left panel). After CS exposure (2 months), EMAPII expression is increased both cellularly and extracellularly, less prominently colocalized with macrophages (arrowheads, middle), and increasingly expressed in parenchyma cells (arrows; right). Scale bar: 100 μm. (C–F) Effect of neutralizing EMAPII (E-AB) or control antibody (IgG) administered by nebulization (50 μg/100 μl) during month 3 of CS exposure on CS-induced lung injury at 4 months. (C) Treatment protocol. (D) Apoptosis detected by caspase-3 activity in lung lysates (caspase units normalized by protein; mean + SEM; *P < 0.05, ANOVA). (E) Number of cells in BALF, and (F) lung static compliance (mean + SEM; *P < 0.01, ANOVA). (G) Representative H&E-stained lung sections (scale bar: 100 μm) showing simplification of lung alveolar structures in response to CS but preserved alveolar architecture when treated with neutralizing EMAPII. (H) Morphometric measurement of MLIs (mean + SEM; *P < 0.05, ANOVA; n = 5–12).