Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension
Background Pulmonary arterial hypertension (PAH) is a deadly disease without effective non-invasive diagnostic and prognostic testing. It remains unclear whether vasodilators reverse inflammatory activation, a part of PAH pathogenesis. Single-cell profiling of inflammatory cells in blood could clari...
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| Format: | Article |
| Language: | English |
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European Respiratory Society
2025-01-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/11/1/00486-2024.full |
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| _version_ | 1849772655739142144 |
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| author | Anna Kirillova Meena Sethuraman Xishuang Dong Almina Kirdar Gil Speyer Yassmin Al Aaraj Annie Watson Lily K. Schneider Michael D. Creager Robert Lafyatis Satoshi Okawa Seungchan Kim Stephen Y. Chan |
| author_facet | Anna Kirillova Meena Sethuraman Xishuang Dong Almina Kirdar Gil Speyer Yassmin Al Aaraj Annie Watson Lily K. Schneider Michael D. Creager Robert Lafyatis Satoshi Okawa Seungchan Kim Stephen Y. Chan |
| author_sort | Anna Kirillova |
| collection | DOAJ |
| description | Background
Pulmonary arterial hypertension (PAH) is a deadly disease without effective non-invasive diagnostic and prognostic testing. It remains unclear whether vasodilators reverse inflammatory activation, a part of PAH pathogenesis. Single-cell profiling of inflammatory cells in blood could clarify these PAH mechanisms.
Methods
We evaluated a University of Pittsburgh Medical Center cohort consisting of idiopathic PAH (iPAH) and systemic sclerosis-associated PAH (sscPAH) patients and non-PAH controls. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from controls (n=3) and from PAH patients (iPAH and sscPAH) naïve to treatment (n=4), PAH patients 3 months after phosphodiesterase-5 inhibitor (PDE5i) treatment (n=7) and PAH patients 3 months after PDE5i+macitentan treatment (n=6). We compared the transcriptomes of five PBMC subtypes from iPAH and sscPAH to observe their serial responses to treatments. Furthermore, we utilised network analysis to illuminate the altered connectivity of biological networks in this complex disease.
Results
We defined differential gene expression and perturbed network connectivity in PBMCs of PAH patients following treatment with PDE5i or PDE5i+macitentan. Importantly, we identified significant reversal of inflammatory transcripts and pathways in the combined PAH patient cohort after vasodilator therapy in every PBMC type assessed. The “glucagon signalling in metabolic regulation” pathway in monocytes was reversed after vasodilator therapy via two independent analysis modalities.
Conclusion
Via a systems-biology approach, we define inflammatory reprogramming in the blood of PAH patients and the anti-inflammatory activity of vasodilators. Such findings establish diagnostic and prognostic blood-based tools for tracking inflammatory progression of PAH and response to therapy. |
| format | Article |
| id | doaj-art-39b41eeb1abf484cad4971b9f38c6802 |
| institution | DOAJ |
| issn | 2312-0541 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj-art-39b41eeb1abf484cad4971b9f38c68022025-08-20T03:02:16ZengEuropean Respiratory SocietyERJ Open Research2312-05412025-01-0111110.1183/23120541.00486-202400486-2024Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertensionAnna Kirillova0Meena Sethuraman1Xishuang Dong2Almina Kirdar3Gil Speyer4Yassmin Al Aaraj5Annie Watson6Lily K. Schneider7Michael D. Creager8Robert Lafyatis9Satoshi Okawa10Seungchan Kim11Stephen Y. Chan12 Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Department of Electrical and Computer Engineering, Center for Computational Systems Biology, Prairie View A&M University, Prairie View, TX, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Research Computing, Arizona State University, Tempe, AZ, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Division of Rheumatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Department of Electrical and Computer Engineering, Center for Computational Systems Biology, Prairie View A&M University, Prairie View, TX, USA Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA Background Pulmonary arterial hypertension (PAH) is a deadly disease without effective non-invasive diagnostic and prognostic testing. It remains unclear whether vasodilators reverse inflammatory activation, a part of PAH pathogenesis. Single-cell profiling of inflammatory cells in blood could clarify these PAH mechanisms. Methods We evaluated a University of Pittsburgh Medical Center cohort consisting of idiopathic PAH (iPAH) and systemic sclerosis-associated PAH (sscPAH) patients and non-PAH controls. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from controls (n=3) and from PAH patients (iPAH and sscPAH) naïve to treatment (n=4), PAH patients 3 months after phosphodiesterase-5 inhibitor (PDE5i) treatment (n=7) and PAH patients 3 months after PDE5i+macitentan treatment (n=6). We compared the transcriptomes of five PBMC subtypes from iPAH and sscPAH to observe their serial responses to treatments. Furthermore, we utilised network analysis to illuminate the altered connectivity of biological networks in this complex disease. Results We defined differential gene expression and perturbed network connectivity in PBMCs of PAH patients following treatment with PDE5i or PDE5i+macitentan. Importantly, we identified significant reversal of inflammatory transcripts and pathways in the combined PAH patient cohort after vasodilator therapy in every PBMC type assessed. The “glucagon signalling in metabolic regulation” pathway in monocytes was reversed after vasodilator therapy via two independent analysis modalities. Conclusion Via a systems-biology approach, we define inflammatory reprogramming in the blood of PAH patients and the anti-inflammatory activity of vasodilators. Such findings establish diagnostic and prognostic blood-based tools for tracking inflammatory progression of PAH and response to therapy.http://openres.ersjournals.com/content/11/1/00486-2024.full |
| spellingShingle | Anna Kirillova Meena Sethuraman Xishuang Dong Almina Kirdar Gil Speyer Yassmin Al Aaraj Annie Watson Lily K. Schneider Michael D. Creager Robert Lafyatis Satoshi Okawa Seungchan Kim Stephen Y. Chan Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension ERJ Open Research |
| title | Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| title_full | Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| title_fullStr | Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| title_full_unstemmed | Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| title_short | Reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| title_sort | reversal of inflammatory reprogramming by vasodilator agents in pulmonary hypertension |
| url | http://openres.ersjournals.com/content/11/1/00486-2024.full |
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