Zongye Cai, Siyu Tian, Theo Klein, Ly Tu, Laurie W. Geenen, Thomas Koudstaal, Annemien E. van den Bosch, Yolanda B. de Rijke, Irwin K. M. Reiss, Eric Boersma, Claude van der Ley, Martijn Van Faassen, Ido Kema, Dirk J. Duncker, Karin A. Boomars, Karin Tran‑Lundmark, Christophe Guignabert, Daphne Merkus
Erasmus MC University Medical Center. Zhejiang University School of Medicine. Hôpital Marie Lannelongue. Sophia Children’s Hospital. University Medical Center Groningen. Lund University. University Clinic Munich.
Netherlands, France, Sweden, Germany and China
Scientific Reports
Sci Rep 2022; 12:
DOI: 10.1038/s41598-022-15039-3
Abstract
Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.
Category
Acquired Patient Factors Associated with Pulmonary Vascular Disease
Potential Biomarkers Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Age Focus: Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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Free PDF File or Full Text Article Available Through PubMed or DOI: Yes