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 1

Lung-specific EMAPII overexpression induces emphysema-like changes.

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Lung-specific EMAPII overexpression induces emphysema-like changes. (A) ...
(A) EMAPII detected by Western blot in BALF (24 hours) and lung lysates after induction with doxycycline (3 weeks); vinculin was used as loading control. Lanes 1, 2, and 3 represent independent lines from either ST (CCSP-rtTA) or DT (EMAPII/CCSP-rtTA) mice. (B) Schematic of transgenic induction (top). EMAPII expression detected in lung cryosections by specific EMAPII polyclonal antiserum immunostaining (green) and DAPI (nuclei, blue) after transgenic induction in ST versus DT mice (3 weeks) (bottom). Note marked alveolar EMAPII staining (arrows) in the DT mice. Scale bar: 50 μm. (C) Caspase-3 activity in lung lysates of ST or DT mice (4 weeks of induction; *P < 0.05, ANOVA). (D) Macrophage counts in the BALF of ST mice or DT mice (6 months; mean + SEM; *P < 0.05, Student’s t test). AM, alveolar macrophage. (E) Representative photomicrographs of Richardson-stained glycol methacrylate lung sections (scale bar: 300 μm) of non–EMAPII-expressing ST CCSP-rtTA (STc) or ST EMAPII (STe) mice compared with EMAPII/CCSP-rtTA mice (DT) after 3 and 6 months of induction, respectively. Note the increase of airspace diameters, consistent with emphysema-like simplification of alveolar structures in DT mice but not in control mice. (F) Morphometry of H&E-stained lungs from ST and DT mice induced for 6 months. Acinar airspace size was expressed as MLI (*P = 0.01, ANOVA; n = 5–6 at 3 months; n = 7–8 at 6 months). (C and F) Lines within the boxes show medians; bounds of the boxes show 25th and the 75th percentiles of the data, respectively; and whiskers show outliers, if applicable (5th and 95th percentiles, respectively).