Role of MicroRNAs in Signaling Pathways Associated with the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Focus on Epithelial-Mesenchymal Transition

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality and unclear etiology. Previous evidence supports that the origin of this disease is associated with epigenetic alterations, age, and environmental factors. IPF initiates with chronic epithelial lung injuries, followed by basal membrane destruction, which promotes the activation of myofibroblasts and excessive synthesis of extracellular matrix (ECM) proteins, as well as epithelial-mesenchymal transition (EMT). Due to miRNAs’ role as regulators of apoptosis, proliferation, differentiation, and cell-cell interaction processes, some studies have involved miRNAs in the biogenesis and progression of IPF. In this context, the analysis and discussion of the probable association of miRNAs with the signaling pathways involved in the development of IPF would improve our knowledge of the associated molecular mechanisms, thereby facilitating its evaluation as a therapeutic target for this severe lung disease. In this work, the most recent publications evaluating the role of miRNAs as regulators or activators of signal pathways associated with the pathogenesis of IPF were analyzed. The search in Pubmed was made using the following terms: “miRNAs and idiopathic pulmonary fibrosis (IPF)”; “miRNAs and IPF and signaling pathways (SP)”; and “miRNAs and IPF and SP and IPF pathogenesis”. Additionally, we focus mainly on those works where the signaling pathways involved with EMT, fibroblast differentiation, and synthesis of ECM components were assessed. Finally, the importance and significance of miRNAs as potential therapeutic or diagnostic tools for the treatment of IPF are discussed.

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery

“…Although fibrotic interstitial lung disease limits the lesion site in the lung, it results in a series of pathological events, among which fibroblast proliferation and differentiation, apoptosis, autophagy, and inflammatory damage may ultimately lead to lung function failure [ 109 ]. Due perhaps to the chronic and progressive nature and severity of lung injury induced by pulmonary fibrosis, several profibrotic miRNAs are downregulated in lung tissue in response to pulmonary fibrosis, as previously shown for miR-21, miR-506, miR-96, miR-499a, miR-326, miR-410, miR-124, miR-328, miR-420, miR-7, miR-19a, miR-19b, miR-26b, miR-9, miR-29, and miR-30a [ 110 , 111 ]. In contrast, other antifibrotic miRNAs, such as miR-30, miR-101, miR-344, miR-323a-3p, miR-29b, miR-185, miR-29a, miR-185, miR-186, miR-221, miR-1343, miR-27a-3p, and miR-27b, are increased [ 110 , 111 ].…”

“…Due perhaps to the chronic and progressive nature and severity of lung injury induced by pulmonary fibrosis, several profibrotic miRNAs are downregulated in lung tissue in response to pulmonary fibrosis, as previously shown for miR-21, miR-506, miR-96, miR-499a, miR-326, miR-410, miR-124, miR-328, miR-420, miR-7, miR-19a, miR-19b, miR-26b, miR-9, miR-29, and miR-30a [ 110 , 111 ]. In contrast, other antifibrotic miRNAs, such as miR-30, miR-101, miR-344, miR-323a-3p, miR-29b, miR-185, miR-29a, miR-185, miR-186, miR-221, miR-1343, miR-27a-3p, and miR-27b, are increased [ 110 , 111 ]. miRNAs have been shown to play an essential role in these pathological events.…”

Exosomal Micro-RNAs as Intercellular Communicators in Idiopathic Pulmonary Fibrosis

“…The release of these molecules induces cellular senescence, activation and proliferation of fibroblasts and their transformation into myofibroblasts, a cell type deeply involved with IPF pathology, and with the decrease in pulmonary function [ 20 , 132 ]. Some of the most studied pathways implicated in the development of fibrosis are TGFβ and WNT pathways, that are also involved with the production of ECM generation of myofibroblasts, and regulation of cell senescence [ 133 ].…”

Construction of a TFs-miRNA-mRNA network related to idiopathic pulmonary fibrosis

“…For example, early growth response transcription factors were found to be key mediators of fibrosis ( 12 ). Moreover, epithelial-mesenchymal transition (EMT) is known as an important feature in IPF and it is regulated by several TFs, which are members of prominent families of master regulators of transcription, such as the Forkhead family ( FOXO ), Twist family ( TWIST ), SNAIL family of zinc-finger transcription factors ( SNAIL ) and zinc-finger E-box-binding family ( ZEB ) ( 13 ). Thus, TFs may play important roles in the development of IPF.…”