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

Matthias Clauss, Robert Voswinckel, Raja Shekhar Gangaraju, 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

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Emphysema
Smoke
Tobacco Products
Monocytes
Lung
Apoptosis
Alveolar Epithelial Cells
Proteins
Transgenic Mice
Up-Regulation
Inflammation
Pulmonary Emphysema
Chemotactic Factors
Bronchoalveolar Lavage Fluid
Caspases
Neutralizing Antibodies
Caspase 3
Chronic Obstructive Pulmonary Disease
Macrophages
Cytokines

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice. / Clauss, Matthias; Voswinckel, Robert; Gangaraju, Raja Shekhar; Sigua, Ninotchka L.; Fehrenbach, Heinz; Rush, Natalia I.; Schweitzer, Kelly S.; Yildirim, Ali Ö; Kamocki, Krzysztof; Fisher, Amanda J.; Gu, Yuan; Safadi, Bilal; Nikam, Sandeep; Hubbard, Walter C.; Tuder, Rubin M.; Twigg, Homer L.; Presson, Robert G.; Sethi, Sanjay; Petrache, Irina.

In: Journal of Clinical Investigation, Vol. 121, No. 6, 01.06.2011, p. 2470-2479.

Research output: Contribution to journalArticle

Clauss, M, Voswinckel, R, Gangaraju, RS, Sigua, NL, Fehrenbach, H, Rush, NI, Schweitzer, KS, Yildirim, AÖ, Kamocki, K, Fisher, AJ, Gu, Y, Safadi, B, Nikam, S, Hubbard, WC, Tuder, RM, Twigg, HL, Presson, RG, 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, vol. 121, no. 6, pp. 2470-2479. https://doi.org/10.1172/JCI43881
Clauss, Matthias ; Voswinckel, Robert ; Gangaraju, Raja Shekhar ; Sigua, Ninotchka L. ; Fehrenbach, Heinz ; Rush, Natalia I. ; Schweitzer, Kelly S. ; Yildirim, Ali Ö ; Kamocki, Krzysztof ; Fisher, Amanda J. ; Gu, Yuan ; Safadi, Bilal ; Nikam, Sandeep ; Hubbard, Walter C. ; Tuder, Rubin M. ; Twigg, Homer L. ; Presson, Robert G. ; Sethi, Sanjay ; Petrache, Irina. / Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 6. pp. 2470-2479.
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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.",
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AU - Voswinckel, Robert

AU - Gangaraju, Raja Shekhar

AU - Sigua, Ninotchka L.

AU - Fehrenbach, Heinz

AU - Rush, Natalia I.

AU - Schweitzer, Kelly S.

AU - Yildirim, Ali Ö

AU - Kamocki, Krzysztof

AU - Fisher, Amanda J.

AU - Gu, Yuan

AU - Safadi, Bilal

AU - Nikam, Sandeep

AU - Hubbard, Walter C.

AU - Tuder, Rubin M.

AU - Twigg, Homer L.

AU - Presson, Robert G.

AU - Sethi, Sanjay

AU - Petrache, Irina

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N2 - 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.

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