Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD

Metabolites

CraigE. Wheelock¹  C.Magnus Sköld¹  Shama Naz²  Sara Ståhl³  Maria Bhat³  ÅsaM. Wheelock⁴  Helena Forsslund⁴ 

[1] Center for Molecular Medicine, Karolinska Institutet, SE 171 77 Stockholm, Sweden;Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden;Research and Development, Innovative Medicines, Personalised Healthcare and Biomarkers, Translational Science Centre, Science for Life Laboratory, AstraZeneca, SE 171 65 Solna, Sweden;;Respiratory Medicine Unit, Department of Medicine Solna &

关键词: tryptophan;    kynurenine;    serotonin;    gender;    smoking;    ido;    copd;   

DOI  :  10.3390/metabo9100212

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown