Dataset Information

Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease.

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.

SUBMITTER: Birnhuber A

PROVIDER: S-EPMC9582508 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease.

Birnhuber Anna A Jandl Katharina K Biasin Valentina V Fließer Elisabeth E Valzano Francesco F Marsh Leigh M LM Krolczik Christina C Olschewski Andrea A Wilhelm Jochen J Toller Wolfgang W Heinemann Akos A Olschewski Horst H Wygrecka Malgorzata M Kwapiszewska Grazyna G

The European respiratory journal 20221020 4

<h4>Background</h4>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.<h4>Methods</h4>Pulmonary function, inflammation and collagen deposition in response to pirfenidone were assessed in Fra-2-overexpressing transgenic (Fra-2 TG) and bleomycin-treated ...[more]

PMID: 35332068

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Project description:Abstract Background and aims: Systemic sclerosis (SSc) is an autoimmune, rare multisystem chronic disease that is still not well-understood aetiologically and is challenging diagnostically. In the literature, there are ever-increasing assumptions regarding the epigenetic mechanisms involved in SSc development; one of them is circulating microRNAs. Many of them regulate TLR pathways and are significant in autoimmune balance. The aim of this study was to determine profile expression of selected microRNAs in SSc patients, including miR-126, -132, -143, -145, -155, -181a, -29a and -3148, in comparison to healthy controls. Methods: Serum microRNAs were isolated from 45 patients with SSc and 57 healthy donors (HC). Additionally, SSc patients were considered in the aspect of disease subtype, including diffuse systemic sclerosis (dcSSc) and limited systemic sclerosis (lcSSc). Results: miR-3148 was detected neither in the serum of HC nor in SSc patients. All of the rest of the analyzed microRNAs, excluding miR-126, miR-29a and miR-181a, were significantly upregulated in SSc patients in comparison to HC. However, miR-181a has been revealed only in the serum of patients with lcSSc but not dcSSc. Moderate positive correlations between the transfer factor of the lung for carbon monoxide (TLCO) and miR-126 and miR-145 were observed. A significant correlation has been found between serum miR-143 level and forced vital capacity (FVC). SSc patients with FVC ≤ 70% were characterized by significantly lower levels of miR-143 compared to patients with normal FVC. Additionally, the expression of miR-132 was significantly higher in dcSSc subgroup with detected active lung lesions compared to dcSSc patients with fibrotic lesions. Patients with an early scleroderma pattern of microangiopathy seen on nailfold video-capillaroscopy (NVC) revealed higher expression of miR-155 in serum than those with a late pattern. Conclusions: The expression profile of circulating cell-free miRNAs is significantly changed in the serum of SSc patients compared to healthy individuals. Downregulation of miRNA-181a and overexpression of miR-132, miR-143, miR-145 and miR-155 in serum may be significant in SSc in the context of biomarkers.

Dataset Information

Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease.

Background

Methods

Results

Conclusion

Publications

Pirfenidone exacerbates Th2-driven vasculopathy in a mouse model of systemic sclerosis-associated interstitial lung disease.

Similar Datasets

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