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 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.

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

“…Nonetheless, 6 months of CS exposure and elastase intratracheal injection increased the Lm of airspace by approximately 19% and 38%, respectively. This was corroborated by the previous findings showing 15%-20% increase of Lm by chronic CS exposure, and 25%-45% increase by elastase administration (45,(47)(48)(49).…”

Pathogenesis of chronic obstructive pulmonary disease

“…Fueled by the identification of increased apoptotic cells in the parenchyma of human emphysema lungs (32), multiple mechanistic studies of the drivers and downstream consequences of this form of regulated cell death have emerged. Although it remains disputed which structural cell of the alveolus directs the process of alveolar destruction, it has been established that (a) apoptosis of both epithelial and endothelial cells occurs in models of emphysema (20,27,33), (b) direct instillation or overexpression in the lung of apoptotic effector molecules induces transient airspace enlargement (33)(34)(35)(36), and (c) specific induction of lung microvascular endothelial cell apoptosis is sufficient to cause a phenotype reminiscent of cigarette smoke-induced emphysema, including influx of inflammatory cells (37). The induction of cell death in structural cells of the lung parenchyma (epithelial, endothelial, and possibly septal fibroblast cells) in response to cigarette smoke may be related to a loss of growth factors, oxidative stress injury, or intracellular response to stress imposed by noxious exposures (e.g., ER stress, ref.…”

Endothelial Monocyte-Activating Polypeptide-Ii: Properties, Functions, and Pathogenetic Significance

“…Крім того, вміст ЕМАР-ІІ значно підвищений при емфіземі, що індукована тютюновим димом, а нейтра-лізація ЕМАР-ІІ антитілами призводить до зменшення запалення, апоптозу альвеолярних клітин, структурних змін в альвеолах, нижніх дихальних шляхах, покращення функції легень. Механізми, що лежать в основі, пов'язані з каспазою-3 [50,51]. Ці результати можуть мати клінічне значен-ня, оскільки вміст ЕМАР-ІІ підвищений як у екс-курців, так і у хворих з хронічними неспецифічними захворюваннями легень, які можуть бути мішенню для терапії нейтра-лізуючими антитілами.…”