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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 Article has an altmetric score of 9

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

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Figure 3

Apoptosis and EMAPII are mutually linked.

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Apoptosis and EMAPII are mutually linked.
(A) Immunoblot of lung EMAPII ...
(A) Immunoblot of lung EMAPII 4 weeks after VEGF receptor inhibitor treatment (VEGFR-inh, 20 mg/kg), (B) quantified as densitometry units normalized to vinculin (mean ± SEM; *P < 0.05 versus control; n = 3/group). Ctrl, control. (C) Lung EMAPII production following active caspase-3 (Casp-3) i.t. (0.8 U; 48 hours) or vehicle treatment (mean densitometry units ± SEM; *P < 0.05 versus control; n = 4/group). (D) Lung caspase-3 activity after recombinant mature EMAPII nebulization (EMAPII i.t.; 50 μg/100 μl; 2 weeks) and caspase inhibitor (Q-VD-OPH, 25 μg/100 μl i.p.) or vehicle (DMSO) treatment, relative to that of controls (saline i.t.). Mean + SEM. *P < 0.05 versus control; #P < 0.05 versus EMAPII plus vehicle; n = 4; ANOVA. (E) Lung EMAPII (proform) production in lung-specific mature EMAPII-overexpressing mice (DT) treated with vehicle or caspase inhibitor 3 times weekly (8 weeks; mean + SEM; *P < 0.05 versus vehicle; n = 4; t test). (F and G) Synergistic effect of EMAPII and CS on lung in EMAPII DT or control (ST) mice induced for 12 weeks, of which the last 4 weeks were combined with CS exposure. (F) EMAPII (mean densitometry units + SEM) and (G) ceramide 16:0 expression normalized by lipid phosphorus (Pi). *P < 0.01; †P < 0.05; n = 4–5. Lines within boxes show medians; bounds of boxes show 25th and 75th percentiles, respectively; and whiskers show 5th and 95th percentiles, respectively. (H) Schematic of apoptosis-anchored feed-forward loop of EMAPII production.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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