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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Birnhuber, A; Jandl, K; Biasin, V; Fließer, E; Valzano, F; Marsh, LM; Krolczik, C; Olschewski, A; Wilhelm, J; Toller, W; Heinemann, A; Olschewski, H; Wygrecka, M; Kwapiszewska, G.
Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease.
Eur Respir J. 2022; 60(4): Doi: 10.1183/13993003.02347-2021 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Birnhuber Anna
Kwapiszewska-Marsh Grazyna
Co-Autor*innen der Med Uni Graz
Biasin Valentina
Fließer Elisabeth
Heinemann Akos
Jandl Katharina
Marsh Leigh
Olschewski Andrea
Olschewski Horst
Toller Wolfgang
Valzano Francesco
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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.
Find related publications in this database (using NLM MeSH Indexing)
Humans - administration & dosage
Mice - administration & dosage
Animals - administration & dosage
Interleukin-4 - pharmacology
Scleroderma, Systemic - complications, drug therapy, metabolism
Bleomycin - pharmacology
Lung Diseases, Interstitial - drug therapy, complications
Lung - pathology
Fibrosis - administration & dosage
Disease Models, Animal - administration & dosage
Inflammation - metabolism
Collagen - metabolism, pharmacology
Cytokines - metabolism
Chemokines - metabolism
Cadherins - metabolism

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