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.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by persistent, largely irreversible airway obstruction caused by chronic inflammation [1,2]
All compounds were detected in all subjects, except for kynurenic acid in one smoker and kynurenine in one COPD ex-smoker, which were below the limit of quantitation (LOQ) and the missing values were replaced with one-third of the LOQ for statistical analysis
Out of the nine identified tryptophan pathway metabolites, the abundance of kynurenine decreased and serotonin increased in healthy smokers and/or COPD smokers compared to the never-smoking population (Figure S1)
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by persistent, largely irreversible airway obstruction caused by chronic inflammation [1,2]. The inflammatory response to cigarette smoke is the major etiological factor, and is an important component driving both the onset of COPD and associated tissue damage in the majority of patients [3]. Previous studies have shown a profound impact of cigarette smoke on T-cells and their release of pro-inflammatory mediators in COPD [4,5,6,7,8]. Tryptophan and its metabolites have been studied in inflammatory and respiratory disease, and found to be altered during infections as part of the immune reaction [11,12,13,14]. The serotonin pathway is catalyzed by tryptophan hydroxylase (TPH), and is further metabolized by monoamine oxidase (MAO) [17]. Cigarette smoke has been shown to inhibit MAO, leading to elevated serotonin levels [22]
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