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Cai, Zongye; Tian, Siyu; Klein, Theo; Tu, Ly; Geenen, Laurie W.; Koudstaal, Thomas; Bosch, Annemien E. van den; Rijke, Yolanda B. de; Reiss, Irwin K. M.; Boersma, Eric; Ley, Claude van der; Faassen, Martijn van; Kema, Ido; Duncker, Dirk J.; Boomars, Karin A.; Tran-Lundmark, Karin; Guignabert, Christophe and Merkus, Daphne (2022): Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6R alpha. In: Scientific Reports, Vol. 12, No. 1, 12326

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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-naive 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-naive 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 alpha (IL-6R alpha) 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-naive PAH patients, likely mediated through IL-6/IL-6R alpha signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

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