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.
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Competing interests: None.
Funding: European Commission Network of Excellence grant QLRT-CT-2001-01407 and a Hellenic Ministry for Development grant GSRT-PENED-136.
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.
See Editorial, p 461
▸ Additional methods data are published online only at http://thorax.bmj.com/content/vol64/issue6