Abstract
BackgroundIdiopathic and toxic pulmonary fibrosis are severe diseases starting classically in the subpleural area of the lung. It has recently been suggested that pleural mesothelial cells acquire a myofibroblast phenotype under fibrotic conditions induced by TGF-β1 or bleomycin. The importance and role of inflammation in fibrogenesis are still controversial. In this work, we explored the role of IL-1β/caspase-1 signaling in bleomycin lung toxicity and in pleural mesothelial cell transformation.MethodsC57BL/6 mice were intravenously injected with either bleomycin or nigericin or NaCl as control. In vitro, the Met5A cell line was used as a model of human pleural mesothelial cells.ResultsIntravenous injections of bleomycin induced lung fibrosis with histologically-proven peripheral distribution, collagen accumulation in the pleural and subpleural area, and overexpression of markers of myofibroblast transformation of pleural cells which migrated into the lung. These events were associated with an inflammatory process with an increase in neutrophil recruitment in pleural lavage fluid and increased caspase-1 activity. TGF-β1 was also overexpressed in pleural lavage fluid and was produced by pleural cells following intravenous bleomycin. In this model, local pleural inhibition of IL-1β with the IL-1β inhibitor anakinra diminished TGF-β1 and collagen accumulation. In vitro, caspase-1 inhibition interfered with Met5A cell transformation into the myofibroblast-like phenotype induced by bleomycin or TGF-β1. Moreover, nigericin, a caspase-1 activator, triggered transformation of Met5A cells and its intra-pleural delivery induced fibrogenesis in mice.ConclusionsWe demonstrated, after intravenous bleomycin injection in mice, the role of the pleura and highlighted the key role of IL-1β/caspase-1 axis in this fibrogenesis process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0475-8) contains supplementary material, which is available to authorized users.
Highlights
Idiopathic and toxic pulmonary fibrosis are severe diseases starting classically in the subpleural area of the lung
We demonstrated, after intravenous bleomycin injection in mice, the role of the pleura and highlighted the key role of IL-1β/caspase-1 axis in this fibrogenesis process
Subpleural fibrosis induced by intravenous bleomycin administration is associated with pleural cell migration Histological analysis of lung sections, quantified by modified Ashcroft scoring and picorsirius red quantification, showed that repeated intravenous injections of bleomycin (BLM) induced progressive subpleural morphological changes in mouse lungs, compared with NaCl controls (Fig. 1a, Additional file 3: Figure S3A, B)
Summary
Idiopathic and toxic pulmonary fibrosis are severe diseases starting classically in the subpleural area of the lung. We explored the role of IL-1β/caspase-1 signaling in bleomycin lung toxicity and in pleural mesothelial cell transformation. The role of mesothelial cells in animal models of pulmonary fibrosis and in human IPF has recently been reported [4,5,6,7,8,9,10,11]. In these diseases, they differentiate into myofibroblast-like cells via a cellular mechanism. The role of caspase-1 on lung structural cells and its involvement during fibrotic processes is still poorly understood
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