Decreased expression of FENDRR, a lung mesenchymal long non-coding RNA, regulates fibroblast phenotypes in IPF through NOX4

Rationale: Myofibroblasts are considered a disease hallmark of idiopathic pulmonary fibrosis (IPF). Recent research indicates the implication of redox imbalance and cellular senescence in the development of myofibroblasts in IPF. Long non-coding RNAs (lncRNAs), a novel class of epigenetic regulators, are attracting attentions as being involved in various biological processes. We recently discovered that FENDRR is among the the most decreased lncRNA in IPF. The aim of study is to test the hypothesis that FENDRR may be involved in myofibroblast differetiation in IPF. Methods & Results: In situ hybridization and immunohistochemistry in the serial sections of IPF lungs revealed that loss of FENDRR associated with increased cellular senescence in myofibroblasts in fibrotic foci. In vitro functional analysis revealed FENDRR depletion by si-RNAs induced differentiation of normal human lung fibroblasts (NHLFs) to myofibroblasts, which was accompanied by the cellular senescence and increased secretion of collagens and inflammatory mediators. We further assessed the involvement of altered redox balance, and found that FENDRR depletion increased intracellular ROS levels with augmented expression of NOX4. Suppression of NOX4 by siRNA reversed the differentiation into myofibroblast as assessed by α-SMA expression in FENDRR-depleted NHLFs. Conclusions: Decreased FENDRR expression may confer the altered phenotypes such as myofibroblastic differentiation and cellular senescence in IPF fibroblasts. Imbalanced redox balance, possibly through increased NOX4 levels may be involved in the mechanism.