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Open AccessArticle

Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD

1
Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden
2
Research and Development, Innovative Medicines, Personalised Healthcare and Biomarkers, Translational Science Centre, Science for Life Laboratory, AstraZeneca, SE 171 65 Solna, Sweden
3
Department of Clinical Neuroscience, Karolinska Institutet, SE 171 77 Stockholm, Sweden
4
Respiratory Medicine Unit, Department of Medicine Solna & Center for Molecular Medicine, Karolinska Institutet, SE 171 77 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Metabolites 2019, 9(10), 212; https://doi.org/10.3390/metabo9100212
Received: 11 July 2019 / Revised: 23 September 2019 / Accepted: 25 September 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Metabolomics and Chronic Obstructive Lung Diseases)
Increased activity of indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase (TPH) have been reported in individuals with chronic obstructive pulmonary disease (COPD). We therefore investigated the effect of gender stratification upon the observed levels of tryptophan metabolites in COPD. Tryptophan, serotonin, kynurenine, and kynurenic acid were quantified in serum of never-smokers (n = 39), smokers (n = 40), COPD smokers (n = 27), and COPD ex-smokers (n = 11) by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). The individual metabolite associations with lung function, blood, and bronchoalveolar lavage (BAL) immune-cell composition, as well as chemokine and cytokine levels, were investigated. Stratification by gender and smoking status revealed that the observed alterations in kynurenine and kynurenic acid, and to a lesser extent serotonin, were prominent in males, irrespective of COPD status (kynurenine p = 0.005, kynurenic acid p = 0.009, and serotonin p = 0.02). Inferred serum IDO activity and kynurenine levels decreased in smokers relative to never-smokers (p = 0.005 and p = 0.004, respectively). In contrast, inferred tryptophan hydroxylase (TPH) activity and serotonin levels showed an increase with smoking that reached significance with COPD (p = 0.01 and p = 0.01, respectively). Serum IDO activity correlated with blood CXC chemokine ligand 9 (CXCL9, p = 0.0009, r = 0.93) and chemokine (C-C motif) ligand 4 (CCL4.(p = 0.04, r = 0.73) in female COPD smokers. Conversely, serum serotonin levels correlated with BAL CD4+ T-cells (%) (p = 0.001, r = 0.92) and CD8+ T-cells (%) (p = 0.002, r = −0.90) in female COPD smokers, but not in male COPD smokers (p = 0.1, r = 0.46 and p = 0.1, r = −0.50, respectively). IDO- and TPH-mediated tryptophan metabolites showed gender-based associations in COPD, which were primarily driven by smoking status. View Full-Text
Keywords: tryptophan; kynurenine; serotonin; gender; smoking; IDO; COPD tryptophan; kynurenine; serotonin; gender; smoking; IDO; COPD
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Naz, S.; Bhat, M.; Ståhl, S.; Forsslund, H.; Sköld, C.M.; Wheelock, Å.M.; Wheelock, C.E. Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD. Metabolites 2019, 9, 212.

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