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 prioritization.
Methods: To decipher a possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed, followed by computerized image analysis. Results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis, utilizing genetically modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analysis was performed ex vivo in mouse embryonic fibroblasts.
Results: Increased GSN expression was detected in lung samples of human idiopathic interstitial pneumonia patients, as well as in modelled pulmonary inflammation and fibrosis. GSN genetic ablation 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.