Kynurenine metabolites predict survival in pulmonary arterial hypertension : A role for IL-6/IL-6Rα
(2022) In Scientific Reports 12.- 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),... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 12
- article number
- 12326
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:35853948
- scopus:85134378105
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-022-15039-3
- language
- English
- LU publication?
- yes
- id
- 00b1c014-130b-48a3-b68a-782017fef4f3
- date added to LUP
- 2022-10-04 12:01:43
- date last changed
- 2024-04-18 10:55:24
@article{00b1c014-130b-48a3-b68a-782017fef4f3,
abstract = {{<p>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.</p>}},
author = {{Cai, Zongye and Tian, Siyu and Klein, Theo and Tu, Ly and Geenen, Laurie W. and Koudstaal, Thomas and van den Bosch, Annemien E. and de Rijke, Yolanda B. and Reiss, Irwin K.M. and Boersma, Eric and van der Ley, Claude and Van Faassen, Martijn and Kema, Ido and Duncker, Dirk J. and Boomars, Karin A. and Tran-Lundmark, Karin and Guignabert, Christophe and Merkus, Daphne}},
issn = {{2045-2322}},
language = {{eng}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{Kynurenine metabolites predict survival in pulmonary arterial hypertension : A role for IL-6/IL-6Rα}},
url = {{http://dx.doi.org/10.1038/s41598-022-15039-3}},
doi = {{10.1038/s41598-022-15039-3}},
volume = {{12}},
year = {{2022}},
}