Ipf‐fibroblast erk1/2 activity is independent from microrna cluster 17‐92 but can be inhibited by treprostinil through dusp1

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP‐β, microRNA cluster 17‐92 (miR17‐92), and Erk1/2 mitogen‐activated protein kinase. This study assessed the role of miR17‐92 in IPF‐fibroblast proliferation and its modification by treprostinil. Fibroblasts were isolated from eight IPF patients, five interstitial lung fibrosis patients, and seven control lungs. Fibroblasts were stimulated with TGF‐β1 over 24 h. The miR17‐92 expression was analyzed by RT‐qPCR, and protein expression by Western blotting. TGF‐β1 upregulated C/EBP‐β in all fibroblasts, which was reduced by treprostinil in control‐fibroblasts, but not in IPF‐fibroblasts. Compared to controls, the guide strands miR‐19a‐3p, miR‐19b‐3p, miR‐20a‐5p, and miR‐92a‐3p, as well as the passenger strands miR‐17‐3p, miR‐18‐3p, miR‐19a‐1‐5p, and miR‐92a‐5p were significantly increased in IPF‐fibro-blasts. In controls, TGF‐β1 and treprostinil significantly reduced specific miR17‐92 members. IPF-fibroblast proliferation was inhibited by treprostinil through increased expression of the Erk1/2 in-hibitor DUSP1. These data suggest that proliferation control via miR17‐92 and C/EBP‐β is disrupted in IPF‐fibroblasts. Therefore, the inhibition of early stages of signaling cascades or specific mitogen receptors might be less effective. However, the increased proliferation is sensitive to Erk1/2 inhibition by treprostinil‐induced DUSP1.