Pleural inhibition of the caspase-1-IL-1β pathway diminishes profibrotic lung toxicity of bleomycinReport as inadecuate

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Respiratory Research

, 17:162

First Online: 29 November 2016Received: 02 August 2016Accepted: 22 November 2016


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.

KeywordsIdiopathic Pulmonary Fibrosis Bleomycin Pleural cells Caspase-1 TGF-β1 AbbreviationsBALFBroncho-alveolar lavage fluid


EMTEpithelial to mesenchymal transition

FISHFluorescence in situ hybridization

HMGB1High mobility group box 1


IPFIdiopathic pulmonary fibrosis

MMTMesothelio-mesenchymal transition

NLRP3NOD-like receptor family, pyrin domain containing 3

PAI-1Plasminogen activator inhibitor-1

PLFPleural lavage fluid

TGF-βTransforming growth factor-β1

α-SMAα-smooth muscle actin

Electronic supplementary materialThe online version of this article doi:10.1186-s12931-016-0475-8 contains supplementary material, which is available to authorized users.

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Author: Olivier Burgy - Pierre-Simon Bellaye - Sebastien Causse - Guillaume Beltramo - Guillaume Wettstein - Pierre-Marie Boutanquoi


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