Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6R alpha

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 und Merkus, Daphne (2022): Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6R alpha. In: Scientific Reports, Bd. 12, Nr. 1, 12326

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-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2045-2322
• Sprache: Englisch