Bronchoalveolar Lavage Fluid from COPD Patients Reveals More Compounds Associated with Disease than Matched Plasma

Abstract

Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography–mass spectrometry (LC–MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10−4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.

Plasma Metabolomic Signatures of Chronic Obstructive Pulmonary Disease and the Impact of Genetic Variants on Phenotype-Driven Modules

“…First, this analysis was performed using blood samples, as opposed to bronchial lavage fluid, which may better represent COPD phenotypes. 33 It is well documented that the blood metabolome, across multiple metabolic pathways, is strongly affected by demographic factors, including age and sex, 51,86 which we replicated in our initial exploratory analyses. COPD pathology begins in the lungs and then manifests as systemic dysregulation across several biologic tissues.…”

Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease

“…urea cycle intermediates) between COPD and healthy individuals. However, analysis of BALF from patients identified a negative association between several amino acids, including arginine and lung function 75 , suggesting that there may be a systemic effect of reduced cofactor levels that does not appear in the faeces. Ncarbamoylglutamate has also been associated with omega-3 fatty acid intake in humans, and a possible link between bacterial production of N-carbamoylglutamate and fatty acids has been suggested 76 ; however, it is currently unknown which bacteria may be producing the compound.…”

Serum Glycerophospholipid Profile in Acute Exacerbation of Chronic Obstructive Pulmonary Disease

“…Cruickshank-Quinn et al used LC-MS to study smokers with COPD and found abnormal expression of several serum glycerophospholipids, among which LPC and PI were significantly negatively correlated with FEV 1 %pred and FEV 1 /FVC; moreover, they also performed integrated transcriptome/metabolome analysis and showed that the expression of LPC, PI, PE, and LPE gradually decreased with worsening lung function outcomes ( Cruickshank-Quinn et al, 2018 ). Halper-Stromberg et al (2019) performed LC-MS analysis of bronchoalveolar lavage fluid (BALF) from COPD patients and showed that the concentrations of lipid metabolites, such as LPC, LPE, and PI, were significantly reduced in COPD patients, and that these metabolites negatively correlated with FEV1/FVC. Furthermore, the level of lipid metabolites in BALF correlated with COPD outcomes more closely than that of serum metabolites.…”