Severity of Lung Function Impairment Drives Transcriptional Phenotypes of COPD and Relates to Immune and Metabolic Processes

Abstract

This study sought to characterize transcriptional phenotypes of COPD through unsupervised clustering of sputum gene expression profiles, and further investigate mechanisms underlying the characteristics of these clusters. Patients and methods: Induced sputum samples were collected from patients with stable COPD (n = 72) and healthy controls (n = 15). Induced sputum was collected for inflammatory cell counts, and RNA extracted. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by GeneSpring GX14.9.1. Unsupervised hierarchical clustering and differential gene expression analysis were performed, and gene alterations validated in the ECLIPSE dataset (GSE22148). Results: We identified 2 main clusters (Cluster 1 [n = 35] and Cluster 2 [n = 37]), which further divided into 4 sub-clusters (Subclusters 1.1 [n = 14], 1.2 [n = 21], 2.1 [n = 20] and 2.2 [n = 17]). Compared with Cluster 1, Cluster 2 was associated with significantly lower lung function (p = 0.014), more severe disease (p = 0.009) and breathlessness (p = 0.035), and increased sputum neutrophils (p = 0.031). Sub-cluster 1.1 had significantly higher proportion of people with comorbid cardiovascular disease compared to the other 3 sub-clusters (92.5% vs 57.1%, 50% and 52.9%, p < 0.013). Through supervised analysis we determined that degree of airflow limitation (GOLD stage) was the predominant factor driving gene expression differences in our transcriptional clusters. There were 452 genes (adjusted p < 0.05 and ≥2 fold) altered in GOLD stage 3 and 4 versus 1 and 2, of which 281 (62%) were also found to be significantly expressed between these GOLD stages in the ECLIPSE data set (GSE22148). Differentially expressed genes were largely downregulated in GOLD stages 3 and 4 and connected in 5 networks relating to lipoprotein and cholesterol metabolism; metabolic processes in oxidation/reduction and mitochondrial function; antigen processing and presentation; regulation of complement activation and innate immune responses; and immune and metabolic processes. Conclusion: Severity of lung function drives 2 distinct transcriptional phenotypes of COPD and relates to immune and metabolic processes.

Combination of click chemistry and Schiff base reaction: Post‐synthesis of covalent organic frameworks as an immobilized metal ion affinity chromatography platform for efficient capture of global phosphopeptides in serum with chronic obstructive pulmonary disease

“…As seen in Figure 6, from a biological perspective, there are significant differences in lipoprotein metabolism and lipid transport between normal human serum and serum from COPD patients. Lipid metabolism is thought to drive different transcriptional phenotypes in COPD in conjunction with gene linkage expression [33], and smoking influences ATP‐binding cassette transporter A1 (ABCA1) gene expression, thereby regulating lipid transport processes in macrophages [34], which is part of the mechanism of inflammatory development in COPD. From a cytological aspect, the Golgi apparatus in the fibroblasts of patients with COPD differs significantly from that of normal subjects [35].…”

Inhibition of CELA1 Improves Septation in the Mouse Hyperoxia Model of Impaired Alveolar Development

“…Since this is a key feature of BPD, future work will require an evaluation of CELA1 levels in the tracheal aspirate fluid of prematurely born infants exposed to hyperoxia. Since previously published microarray data in chronic obstructive pulmonary disease detected higher CELA1 levels in the sputum of subjects with advanced stage COPD (28, 29), it may be feasible to directly measure CELA1 mRNA in the tracheal aspirates of intubated prematurely born infants to test for an association with inspired oxygen levels.…”