Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis

Arthritis Research & Therapy

Research

Dominique Rongvaux-Gaïda¹  François Rieger¹  Ly Tu²  Christophe Guignabert²  Mina Ottaviani²  Raphaël Thuillet²  Anne Cauvet³  Arthur Decellas³  Yannick Allanore⁴  Jérôme Avouac⁴ 

[1] MEDSENIC SAS, Strasbourg, France;UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, INSERM, Hôpital Marie Lannelongue, Le Plessis-Robinson, France;Faculté de Médecine, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Université Paris-Saclay, Le Kremlin-Bicêtre, France;Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104, 75014, Paris, France;Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104, 75014, Paris, France;Rheumatology Department, Université de Paris, Cochin Hospital, Paris, France;

关键词: Systemic sclerosis;    Arsenic trioxide;    Pulmonary fibrosis;    Pulmonary hypertension;   

DOI  :  10.1186/s13075-023-03143-2

 received in 2023-05-25, accepted in 2023-08-22,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundUncontrolled T-cell activation plays a key role in systemic sclerosis (SSc). Arsenic trioxide (ATO) has immunological effects and has demonstrated potential in preclinical SSc models. In this study, we assessed the efficacy of ATO in Fra2 transgenic (Fra2TG) mice, which develop severe vascular remodeling of pulmonary arterioles and nonspecific interstitial pneumonia-like lung disease, closely resembling human SSc-associated pulmonary hypertension, therefore partially resembling to the SSc human disease.MethodsThe efficacy of ATO in Fra2TG mice was evaluated through histological scoring and determination of cell infiltration. Fibrotic changes in the lungs were assessed by measuring collagen content biochemically, using second harmonic generation to measure fibrillar collagen, and imaging via computed tomography. Cardiovascular effects were determined by measuring right ventricular systolic pressure and vessel remodeling. The mechanism of action of ATO was then investigated by analyzing lung cell infiltrates using flow cytometry and bulk RNA with sequencing techniques.ResultsAfter ATO treatment, the Ashcroft histological score was substantially decreased by 33% in ATO-treated mice compared to control mice. Other investigations of fibrotic markers showed a trend of reduction in various measurements of fibrosis, but the differences did not reach significance. Further cardiovascular investigations revealed convergent findings supporting a beneficial effect of ATO, with reduced right ventricular systolic pressure and medial wall thickness, and a significant decrease in the number of muscularized distal pulmonary arteries in ATO-treated Fra2TG mice compared to untreated Fra2TG mice. Additionally, inflammatory cell infiltration was also markedly reduced in lesioned lungs. A reduction in the frequency of CD4 + and T effector memory cells, and an increase in the percentage of CD4 + T naive cells in the lungs of ATO-treated Fra-2TG mice, was observed when compared to PBS group Fra-2Tg mice. RNA-seq analysis of ATO-treated mouse lungs revealed a downregulation of biological pathways associated with immune activity and inflammation, such as T-cell activation, regulation of leucocyte activation, leucocyte cell–cell adhesion, and regulation of lymphocyte activation.ConclusionsOur results suggest the clinical relevance of ATO treatment in SSc. Using the Fra2TG mouse model, we observed significant lung histological changes, a trend towards a decrease in various fibrotic makers, and a strong reduction in vascular remodeling. The mechanism of action of ATO appears to involve a marked counteraction of the immune activation characteristic of SSc, particularly T-cell involvement. These findings pave the way for further studies in SSc.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

Fig. 3

Fig. 1

12936_2023_4724_Article_IEq72.gif

13690_2023_1177_Figc_HTML.png

13690_2023_1170_Article_IEq6.gif

Fig. 4

Fig. 3