TRPA1 Regulates Fibrosis‐Associated Transcriptional Pathways in Human Lung Epithelial Cells
TL;DR
Next‐generation sequencing and STRING network analysis suggest that TRPA1 regulates fibrosis‐related genes through FOS gene and AP‐1 transcription factor and propose TRPA1 as a factor and therapeutic target in fibrotic lung diseases, which are associated with poor survival and critical need for novel disease‐modifying therapies.
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a cation channel originally identified in lung fibroblasts and extensively studied in sensory neurons, where it is associated with pain and neurogenic inflammation. We and others have recently shown that TRPA1 is also expressed in lung epithelial cells and that its expression is regulated by the cytokine environment. In the present study, we used next‐generation sequencing to analyse the role of TRPA1 and the effects of its inhibition on human A549 lung epithelial cell phenotype under inflammatory conditions. Two different TRPA1 inhibitors (HC‐030031 and A‐967079) were used and found to alter the expression of 968 genes: 576 genes were downregulated, and 392 upregulated. Ingenuity Pathway Analysis (IPA) predicted that TRPA1 inhibitors significantly suppress the activity of pulmonary fibrosis idiopathic signalling and wound healing pathways. In these pathways, altered genes included matrix metalloproteinases (MMPs), growth factors, collagens and transcription factors. The major profibrotic mediators MMP‐12 and MMP‐7 were among the most strongly inhibited genes by TRPA1 inhibitors. STRING network analysis suggests that TRPA1 regulates fibrosis‐related genes through FOS gene and AP‐1 transcription factor. These findings together with previous data propose TRPA1 as a factor and therapeutic target in fibrotic lung diseases, which are associated with poor survival and critical need for novel disease‐modifying therapies.