title: 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.affiliation: Indiana Center for Vascular Biology and Medicine and Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, Indiana 46202, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Gangaraju
authors.initials: G
authors.lastname: Rajashekhar
authors.forename: Ninotchka L
authors.initials: NL
authors.lastname: Sigua
authors.forename: Heinz
authors.initials: H
authors.lastname: Fehrenbach
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Rush
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.forename: Ali Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gu
authors.forename: Bilal
authors.initials: B
authors.lastname: Safadi
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nikam
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Homer L
authors.initials: HL
authors.lastname: Twigg
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D017209:Apoptosis; D001273:Atmosphere Exposure Chambers; D055745:Bronchioles / Q000187:drug effects / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053148:Caspase 3 / Q000633:toxicity; D061945:Caspase Inhibitors; D016207:Cytokines / Q000502:physiology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007116:Immunization, Passive; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000502:physiology* / Q000627:therapeutic use; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology* / Q000627:therapeutic use; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D061945:Caspase Inhibitors; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D014028:Tobacco Smoke Pollution; C077219:small inducible cytokine subfamily E, member 1; D053148:Caspase 3