TY - JOUR T1 - Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of SSc-ILD JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.02347-2021 SP - 2102347 AU - Anna Birnhuber AU - Katharina Jandl AU - Valentina Biasin AU - Elisabeth Fließer AU - Francesco Valzano AU - Leigh M Marsh AU - Christina Krolczik AU - Andrea Olschewski AU - Jochen Wilhelm AU - Wolfgang Toller AU - Akos Heinemann AU - Horst Olschewski AU - Malgorzata Wygrecka AU - Grazyna Kwapiszewska Y1 - 2022/01/01 UR - http://erj.ersjournals.com/content/early/2022/03/17/13993003.02347-2021.abstract N2 - Systemic sclerosis (SSc) is an autoimmune disease characterised by severe vasculopathy and fibrosis of various organs including the lung. Targeted treatment options for SSc-associated interstitial lung disease (SSc-ILD) are scarce. Here we assessed the effects of pirfenidone in a mouse model of SSc-ILD.Pulmonary function, inflammation and collagen deposition in response to pirfenidone were assessed in Fra-2-overexpressing (Fra-2 TG) and bleomycin-treated mice. In Fra-2 TG mice, lung transcriptome was analysed after pirfenidone treatment. In vitro, pirfenidone effects on human eosinophil and endothelial cell function were analysed using flow cytometry-based assays and electric cell-substrate impedance measurements, respectively.Pirfenidone treatment attenuated pulmonary remodelling in the bleomycin-model, but aggravated pulmonary inflammation, fibrosis, and vascular remodelling in Fra-2 TG mice. Pirfenidone increased interleukin (IL)-4 levels and eosinophil numbers in lung tissue of Fra-2 TG mice without directly affecting eosinophil activation and migration in vitro. A pronounced immune response with high levels of cytokines/chemokines and disturbed endothelial integrity with low VE-cadherin levels were observed in pirfenidone-treated Fra-2 TG mice. In contrast, eosinophil, IL-4 and VE-cadherin levels were unchanged in bleomycin-treated mice and not influenced by pirfenidone. In vitro, pirfenidone exacerbated the IL-4 induced reduction of endothelial barrier resistance leading to higher leukocyte transmigration.This study shows that anti-fibrotic properties of pirfenidone may be overruled by unwanted interactions with pre-injured endothelium in a setting of high Th2 inflammation in a model of SSc-ILD. Careful ILD patient phenotyping may be required to exploit benefits of pirfenidone while avoiding therapy failure and additional lung damage in some patients.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. ER -