title: Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome.
abstract: BACKGROUND
  Activin-A is up-regulated in various respiratory disorders. However, its precise role in pulmonary pathophysiology has not been adequately substantiated in vivo.
  
  
  OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Center for Immunology and Transplantation, Athens, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Apostolou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stavropoulos
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sountoulidis
authors.forename: Charoula
authors.initials: C
authors.lastname: Xirakia
authors.forename: Stavros
authors.initials: S
authors.lastname: Giaglis
authors.forename: Evdokia
authors.initials: E
authors.lastname: Protopapadakis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ritis
authors.forename: Spyros
authors.initials: S
authors.lastname: Mentzelopoulos
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.forename: Martyn
authors.initials: M
authors.lastname: Foster
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.forename: George E
authors.initials: GE
authors.lastname: Tzelepis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
authors.forename: Paschalis
authors.initials: P
authors.lastname: Sideras
mesh_terms: D030301:Activin Receptors, Type II / Q000627:therapeutic use; D028341:Activins / Q000032:analysis / Q000378:metabolism*; D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D024243:HMGB1 Protein; D011993:Recombinant Fusion Proteins; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B