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.
- Birnhuber, A.
- Jandl, K.
- Biasin, V.
- Fließer, E.
- Valzano, F.
- Marsh, L. M.
- Krolczik, C.
- Olschewski, A.
- Wilhelm, J.
- Toller, W.
- Heinemann, A.
- Olschewski, H.
- Wygrecka, M.
- Kwapiszewska, G.
