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.
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.
Authors: Wouter N Leonhard; Steven J Kunnen; Anna J Plugge; Arja Pasternack; Sebastian B T Jianu; Kimberley Veraar; Fatiha El Bouazzaoui; Willem M H Hoogaars; Peter Ten Dijke; Martijn H Breuning; Emile De Heer; Olli Ritvos; Dorien J M Peters Journal: J Am Soc Nephrol Date: 2016-03-28 Impact factor: 10.121
Authors: David Morritz de Kretser; Jonathan Guy Bensley; Ville Pettilä; Rita Linko; Mark Peter Hedger; Susan Hayward; Carolyn Anne Allan; Robert Ian McLachlan; Helen Ludlow; David James Phillips Journal: Crit Care Date: 2013-10-31 Impact factor: 9.097
Authors: Jason Roh; Robert Kitchen; J Sawalla Guseh; Jenna McNeill; Malika Aid; Amanda Martinot; Andy Yu; Colin Platt; James Rhee; Brittany Weber; Lena Trager; Margaret Hastings; Sarah Ducat; Peng Xia; Claire Castro; Bjarni Atlason; Timothy Churchill; Marcelo Di Carli; Patrick Ellinor; Dan Barouch; Jennifer Ho; Anthony Rosenzweig Journal: Res Sq Date: 2021-06-08
Authors: Richard G James; Stephen R Reeves; Kaitlyn A Barrow; Maria P White; Veronika A Glukhova; Candace Haghighi; Dana Seyoum; Jason S Debley Journal: Am J Respir Cell Mol Biol Date: 2018-07 Impact factor: 7.748
Authors: Charles L Hardy; Susannah J King; Nicole A Mifsud; Mark P Hedger; David J Phillips; Fabienne Mackay; David M de Kretser; John W Wilson; Jennifer M Rolland; Robyn E O'Hehir Journal: Immunol Cell Biol Date: 2015-03-10 Impact factor: 5.126
Authors: Rita Linko; Mark P Hedger; Ville Pettilä; Esko Ruokonen; Tero Ala-Kokko; Helen Ludlow; David M de Kretser Journal: BMC Infect Dis Date: 2014-05-10 Impact factor: 3.090