RESUMO
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.
Assuntos
Citocinas/fisiologia , Proteínas de Neoplasias/fisiologia , Enfisema Pulmonar/genética , Proteínas de Ligação a RNA/fisiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Animais , Anticorpos Neutralizantes/uso terapêutico , Apoptose , Câmaras de Exposição Atmosférica , Bronquíolos/efeitos dos fármacos , Bronquíolos/patologia , Líquido da Lavagem Broncoalveolar/química , Caspase 3/toxicidade , Inibidores de Caspase , Citocinas/uso terapêutico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Imunização Passiva , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas de Neoplasias/uso terapêutico , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Proteínas de Ligação a RNA/uso terapêutico , Ratos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/fisiologia , Proteínas Recombinantes de Fusão/uso terapêutico , Fumar/efeitos adversos , Fumar/metabolismo , Adulto JovemRESUMO
BACKGROUND: Fragmented QRS complexes (fQRS) on a 12-lead ECG are a marker of myocardial scar in patients with coronary artery disease. Cardiac sarcoidosis is also associated with myocardial granuloma formation and scarring. We evaluated the significance of fQRS on a 12-lead ECG compared to Gadolinium-delayed enhancement images (GDE) in cardiac magnetic resonance imaging (CMR). METHOD AND RESULTS: The ECGs of patients (n = 17, mean age: 52 +/- 11 years, male: 53%) with established diagnosis of sarcoidosis who underwent a CMR for evaluation of cardiac involvement were studied. ECG abnormalities included bundle branch block, Q wave, and fQRS. fQRS, Q wave, and bundle branch block were present in 9 (53%), 1 (6%), and 4 (24%) patients, respectively. The sensitivity and specificity of fQRS for detecting abnormal GDE were 100% and 80%, respectively. Sensitivity and specificity of Q waves were 11% and 100%, respectively. CONCLUSIONS: fQRS on a 12-lead ECG in patients with suspected cardiac sarcoidosis are associated with cardiac involvement as detected by GDE on CMR.