@article{3152589,
    title = "Activin-A Overexpression in the Murine Lung Causes Pathology That
Simulates Acute Respiratory Distress Syndrome",
    author = "Apostolou, Eirini and Stavropoulos, Athanasios and Sountoulidis, and Alexandros and Xirakia, Charoula and Giaglis, Stavros and and Protopapadakis, Evdokia and Ritis, Konstantinos and Mentzelopoulos, and Spyros and Pasternack, Arja and Foster, Martyn and Ritvos, Olli and and Tzelepis, George E. and Andreakos, Evangelos and Sideras, Paschalis",
    journal = "AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE",
    year = "2012",
    volume = "185",
    number = "4",
    pages = "382-391",
    publisher = "AMER THORACIC SOC",
    issn = "1073-449X",
    doi = "10.1164/rccm.201105-0784OC",
    keywords = "Activin-A; ALI; ARDS; inflammation; mouse model",
    abstract = "Rationale: Activin-A is up-regulated in various respiratory disorders.
However, its precise role in pulmonary pathophysiology has not been
adequately substantiated in vivo.
Objectives: To investigate in vivo the consequences of dysregulated
Activin-A expression in the lung and identify key Activin-A-induced
processes that contribute to respiratory pathology.
Methods: Activin-A was ectopically expressed in murine lung, and
functional, structural, and molecular alterations were extensively
analyzed. The validity of Activin-A as a therapeutic target was
demonstrated in animals overexpressing Activin-A or treated with
intratracheal instillation of LPS. Relevancy to human pathology was
substantiated by demonstrating high Activin-A levels in bronchoalveolar
lavage (BAL) samples from patients with acute respiratory distress
syndrome (ARDS).
Measurements and Main Results: Overexpression of Activin-A in mouse
airways caused pulmonary pathology reminiscent of acute lung injury
(ALI)/ARDS. Activin-A triggered a lasting inflammatory response
characterized by acute alveolar cell death and hyaline membrane
formation, sustained up-regulation of high-mobility group box 1,
development of systemic hypercoagulant state, reduction of surfactant
proteins SpC, SpB, and SpA, decline of lung compliance, transient
fibrosis, and eventually emphysema. Therapeutic neutralization of
Activin-A attenuated the ALI/ARDS-like pathology induced either by
ectopic expression of Activin-A or by intratracheal instillation of LPS.
In line with the similarity of the Activin-A-induced phenotype to human
ARDS, selective up-regulation of Activin-A was found in BAL of patients
with ARDS.
Conclusions: Our studies demonstrate for the first time in vivo the
pathogenic consequences of deregulated Activin-A expression in the lung,
document novel aspects of Activin-A biology that provide mechanistic
explanation for the observed phenotype, link Activin-A to ALI/ARDS
pathophysiology, and provide the rationale for therapeutic targeting of
Activin-A in these disorders."
}