Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome

Am J Respir Crit Care Med. 2012 Feb 15;185(4):382-91. doi: 10.1164/rccm.201105-0784OC. Epub 2011 Dec 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / therapeutic use
  • Activins / analysis
  • Activins / metabolism*
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Disease Models, Animal
  • Female
  • HMGB1 Protein / metabolism
  • Humans
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Recombinant Fusion Proteins / therapeutic use
  • Respiratory Distress Syndrome / drug therapy
  • Respiratory Distress Syndrome / metabolism*
  • Respiratory Distress Syndrome / pathology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Up-Regulation

Substances

  • HMGB1 Protein
  • Recombinant Fusion Proteins
  • activin A
  • Activins
  • Activin Receptors, Type II
  • activin receptor type II-B