Co-Expression Analysis of Airway Epithelial Transcriptome in Asthma Patients with Eosinophilic vs. Non-Eosinophilic Airway Infiltration

Abstract

Asthma heterogeneity complicates the search for targeted treatment against airway inflammation and remodeling. We sought to investigate relations between eosinophilic inflammation, a phenotypic feature frequent in severe asthma, bronchial epithelial transcriptome, and functional and structural measures of airway remodeling. We compared epithelial gene expression, spirometry, airway cross-sectional geometry (computed tomography), reticular basement membrane thickness (histology), and blood and bronchoalveolar lavage (BAL) cytokines of n = 40 moderate to severe eosinophilic (EA) and non-eosinophilic asthma (NEA) patients distinguished by BAL eosinophilia. EA patients showed a similar extent of airway remodeling as NEA but had an increased expression of genes involved in the immune response and inflammation (e.g., KIR3DS1), reactive oxygen species generation (GYS2, ATPIF1), cell activation and proliferation (ANK3), cargo transporting (RAB4B, CPLX2), and tissue remodeling (FBLN1, SOX14, GSN), and a lower expression of genes involved in epithelial integrity (e.g., GJB1) and histone acetylation (SIN3A). Genes co-expressed in EA were involved in antiviral responses (e.g., ATP1B1), cell migration (EPS8L1, STOML3), cell adhesion (RAPH1), epithelial–mesenchymal transition (ASB3), and airway hyperreactivity and remodeling (FBN3, RECK), and several were linked to asthma in genome- (e.g., MRPL14, ASB3) or epigenome-wide association studies (CLC, GPI, SSCRB4, STRN4). Signaling pathways inferred from the co-expression pattern were associated with airway remodeling (e.g., TGF-β/Smad2/3, E2F/Rb, and Wnt/β-catenin).

Recent Developments in the Role of Histone Acetylation in Asthma

“…In airway fibroblasts, expression levels of only a single enzyme (histone methyltransferase) differed between subjects with and without asthma, but this difference was not resistant to the adjustment for multiple testing [60]. Interestingly, differential patterns of 15 out of 32 genes, as observed between AECs obtained from subjects with eosinophilic versus noneosinophilic asthma, matched those reported in human lung fibroblasts as associated with patterns of histone modifications such as H3K9 acetylation (and H3K27 trimethylation) [61]. Besides, endothelin-1 was demonstrated to reduce HDAC2 activity and thus increase H3 acetylation, ultimately leading to higher expression of connective tissue growth factor in the human fetal lung fibroblast cell line WI-38 [62].…”