Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD

Abstract

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.

<p>Chronic Obstructive Pulmonary Disease in Women: A Biologically Focused Review with a Systematic Search Strategy</p>

“…Further quantification of tryptophan and metabolites (serotonin, kynurenine, and kynurenic acid) by LC-MS/ MS in this cohort was also performed. 53 In this exploratory analysis of 38 participants with COPD, 39 neversmokers and 40 smokers without COPD, major differences between tryptophan and metabolites were not seen between men and women. However, an increase in serum serotonin in women better correlated with BAL CD4+ and CD8+ T-cell counts in female but not male smokers suggesting a potential difference in inflammatory pathways as outlined above.…”

Smoking-associated increase in mucins 1 and 4 in human airways

“…Also, a major limitation is that the study is based only on biopsies from the large airways. In spite of these concerns, the results are significant, and the gender differences are supported by other data blocks from the same cohort [21][22][23][24][25][26][27][28][29][30].…”

“…The investigations were performed on specimens from the Karolinska COSMIC cohort (Clinical & Systems Medicine Investigations of Smoking-related Chronic Obstructive Pulmonary Disease) (www.ClinicalTrials.gov/ ct2/show/study/NCT02627872). The cohort has been described in detail previously [21][22][23][24][25][26][27][28][29][30]. The demographics of the included subjects are summarized in Table 1.…”

Untargeted Urinary Metabolomics and Children’s Exposure to Secondhand Smoke: The Influence of Individual Differences

“…The results from our study suggested a positive relation between kynurenine and tyrosyl-tryptophan and SHS exposure. The kynurenine pathway is responsible for tryptophan metabolism, and 95% of tryptophan is metabolized via the kynurenine pathway [ 38 ]. Therefore, our results suggest a pivotal relationship between tryptophan/kynurenine metabolism and children’s exposure to SHS.…”

“…However, there are also studies showing the opposite conclusion. Naz et al found that in chronic obstructive pulmonary disease (COPD) patients, the level of kynurenine, which is the main product of tryptophan [ 44 ], decreased in smokers relative to never-smokers [ 38 ]. Mathai et al [ 45 ] reported that in schizophrenic patients, current smokers showed lower kynurenine levels than past smokers, which further elucidates the neurobiological underpinnings of altered kynurenine levels in smokers.…”