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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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) na\u00efve to treatment (n=4), PAH patients 3\u2005months after phosphodiesterase-5 inhibitor (PDE5i) treatment (n=7) and PAH patients 3\u2005months 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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 \u201cglucagon signalling in metabolic regulation\u201d pathway in monocytes was reversed after vasodilator therapy<jats:italic>via<\/jats:italic>two independent analysis modalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Via<\/jats:italic>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.<\/jats:p><\/jats:sec>","DOI":"10.1183\/23120541.00486-2024","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:30:48Z","timestamp":1723131048000},"page":"00486-2024","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Reversal of inflammatory reprogramming by vasodilator agents in pulmonary 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