Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis
- N Oikonomou1,
- A Thanasopoulou1,
- A Tzouvelekis2,
- V Harokopos1,
- T Paparountas1,
- I Nikitopoulou1,
- W Witke3,
- A Karameris4,
- A Kotanidou5,
- D Bouros2,
- V Aidinis1
- 1Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
- 2Department of Pneumonology, Democritus University of Thrace, Medical School and University Hospital of Alexandroupolis, Alexandroupolis, Greece
- 3Mouse Biology Programme, European Molecular Biology Laboratory, Monterotondo, Italy
- 4Department of Pathology, Veterans Administration Hospital (NIMTS), Athens, Greece
- 5First Department of Critical Care, University of Athens Medical School, Athens, Greece
- Dr V Aidinis, Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, 34 Fleming Street, 16672 Athens, Greece; v.aidinis{at}fleming.gr
- Received 12 September 2008
- Accepted 21 January 2009
- Published Online First 12 February 2009
Abstract
Background: Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation.
Methods: To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts.
Results: Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis.
Conclusions: Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.
Footnotes
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Competing interests: None.
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Funding: European Commission Network of Excellence grant QLRT-CT-2001-01407 and a Hellenic Ministry for Development grant GSRT-PENED-136.
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Ethics approval: Following protocol approval by the local ethics committee (#1669), all patients signed an informed consent form where they agreed to the anonymous usage of their lung samples for research purposes. All experimentation was approved by an internal Institutional Review Board, as well as by the Veterinary Service and Fishery Department of the local governmental prefecture.
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See Editorial, p 461
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‣ Additional methods data are published online only at http://thorax.bmj.com/content/vol64/issue6
