Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab 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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Leading authors Med Uni Graz

Birnhuber Anna

Kwapiszewska-Marsh Grazyna

Co-authors 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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