Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease. Issue 4 (20th October 2022)

• Record Type: Journal Article
• Authors: Birnhuber, Anna; Jandl, Katharina; Biasin, Valentina; Fließer, Elisabeth; Valzano, Francesco; Marsh, Leigh M.; Krolczik, Christina; Olschewski, Andrea; Wilhelm, Jochen; Toller, Wolfgang; Heinemann, Akos; Olschewski, Horst; Wygrecka, Malgorzata; Kwapiszewska, Grazyna
• Is Part Of: European respiratory journal. Volume 60:Issue 4(2022)
• Publication Date: 2022-10-20
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.02347-2021
• Languages: English
• ISSNs: 0903-1936

Abstract

Background: 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. We assessed the effects of pirfenidone in a mouse model of SSc-ILD. Methods: Pulmonary function, inflammation and collagen deposition in response to pirfenidone were assessed in Fra-2-overexpressing transgenic (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. Results: 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 vascular endothelial (VE)-cadherin levels was observed in pirfenidone-treated Fra-2 TG mice. In contrast, eosinophil 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. Conclusion: This study shows that antifibrotic properties of pirfenidone may be overruled by unwanted interactions with pre-injured endothelium in a setting of high T-helper type 2 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. Pirfenidone worsens vascular and pulmonary dysfunction in a SSc-ILD mouse model due to its negative effects on primed endothelial cells and may lead to unfavourable effects in patients with underlying type 2 inflammation as seen in SSc-ILD https://bit.ly/3Jk821j