Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis
Abstract Background Uncontrolled 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 s...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-023-03143-2 |
| _version_ | 1827633553757700096 |
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| author | Anne Cauvet Arthur Decellas Christophe Guignabert Dominique Rongvaux-Gaïda Raphaël Thuillet Mina Ottaviani Ly Tu François Rieger Jérôme Avouac Yannick Allanore |
| author_facet | Anne Cauvet Arthur Decellas Christophe Guignabert Dominique Rongvaux-Gaïda Raphaël Thuillet Mina Ottaviani Ly Tu François Rieger Jérôme Avouac Yannick Allanore |
| author_sort | Anne Cauvet |
| collection | DOAJ |
| description | Abstract Background Uncontrolled 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. Methods The 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. Results After 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. Conclusions Our 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. |
| first_indexed | 2024-03-09T15:01:10Z |
| format | Article |
| id | doaj.art-9484ca97d3e341f0936d1ff2ac44b633 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-09T15:01:10Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-9484ca97d3e341f0936d1ff2ac44b6332023-11-26T13:54:32ZengBMCArthritis Research & Therapy1478-63622023-09-0125111210.1186/s13075-023-03143-2Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosisAnne Cauvet0Arthur Decellas1Christophe Guignabert2Dominique Rongvaux-Gaïda3Raphaël Thuillet4Mina Ottaviani5Ly Tu6François Rieger7Jérôme Avouac8Yannick Allanore9Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, INSERM, Hôpital Marie LannelongueMEDSENIC SASUMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, INSERM, Hôpital Marie LannelongueUMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, INSERM, Hôpital Marie LannelongueUMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, INSERM, Hôpital Marie LannelongueMEDSENIC SASUniversité de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104Abstract Background Uncontrolled 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. Methods The 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. Results After 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. Conclusions Our 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.https://doi.org/10.1186/s13075-023-03143-2Systemic sclerosisArsenic trioxidePulmonary fibrosisPulmonary hypertension |
| spellingShingle | Anne Cauvet Arthur Decellas Christophe Guignabert Dominique Rongvaux-Gaïda Raphaël Thuillet Mina Ottaviani Ly Tu François Rieger Jérôme Avouac Yannick Allanore Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis Arthritis Research & Therapy Systemic sclerosis Arsenic trioxide Pulmonary fibrosis Pulmonary hypertension |
| title | Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| title_full | Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| title_fullStr | Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| title_full_unstemmed | Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| title_short | Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| title_sort | arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis |
| topic | Systemic sclerosis Arsenic trioxide Pulmonary fibrosis Pulmonary hypertension |
| url | https://doi.org/10.1186/s13075-023-03143-2 |
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