title: Pleural inhibition of the caspase-1/IL-1β pathway diminishes profibrotic lung toxicity of bleomycin.
abstract: Idiopathic 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.
  
  
  
  C57BL/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.
  
  
  
  Intravenous 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.
  
  
  
  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.
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Burgy
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Bellaye
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Causse
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.|Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalo-Universitaire de Bourgogne, 21000, Dijon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Beltramo
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Wettstein
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Boutanquoi
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Goirand
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France.|Anticancer Centre Georges François Leclerc, CGFL, 21000, Dijon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: INSERM, LNC UMR866, LipSTIC LabEx team, Université Bourgogne Franche-Comté, 21000, Dijon, France. philippe.bonniaud@chu-dijon.fr.|Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalo-Universitaire de Bourgogne, 21000, Dijon, France. philippe.bonniaud@chu-dijon.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonniaud
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001761:Bleomycin; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009550:Nigericin / Q000494:pharmacology; D010994:Pleura / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D061945:Caspase Inhibitors; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D020170:Caspase 1; D009550:Nigericin
keywords: Bleomycin; Caspase-1; Idiopathic Pulmonary Fibrosis; Pleural cells; TGF-β1