TY - JOUR
TI - Activin-A Overexpression in the Murine Lung Causes Pathology That
Simulates Acute Respiratory Distress Syndrome
AU - Apostolou, Eirini
AU - Stavropoulos, Athanasios
AU - Sountoulidis,
AU - Alexandros
AU - Xirakia, Charoula
AU - Giaglis, Stavros and
AU - Protopapadakis, Evdokia
AU - Ritis, Konstantinos
AU - Mentzelopoulos,
AU - Spyros
AU - Pasternack, Arja
AU - Foster, Martyn
AU - Ritvos, Olli and
AU - Tzelepis, George E.
AU - Andreakos, Evangelos
AU - Sideras, Paschalis
JO - AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
PY - 2012
VL - 185
TODO - 4
SP - 382-391
PB - AMER THORACIC SOC
SN - 1073-449X
TODO - 10.1164/rccm.201105-0784OC
TODO - Activin-A; ALI; ARDS; inflammation; mouse model
TODO - 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.
ER -