Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. During the past decade, novel pathogenic mechanisms of IPF have been elucidated that have shifted the concept of IPF from an inflammatory-driven to an epithelial-driven disease. Dysregulated repair responses induced by recurrent epithelial cell damage and excessive extracellular matrix accumulation result in pulmonary fibrosis. Although there is currently no curative therapy for IPF, two medications, pirfenidone and nintedanib, have been introduced based on understanding the pathogenesis of the disease. In this review, we discuss advances in understanding IPF pathogenesis, highlighting epithelial-mesenchymal transition (EMT), the ubiquitin-proteasome system, and endothelial cells. TGF-β is a central regulator involved in EMT and pulmonary fibrosis. HECT-, RING finger-, and U-box-type E3 ubiquitin ligases regulate TGF-β-Smad pathway-mediated EMT via the ubiquitin-proteasome pathway. p27 degradation mediated by the SCF-type E3 ligase, Skp2, contributes to the progression of pulmonary fibrosis by promotion of either mesenchymal fibroblast proliferation, EMT, or both. In addition to fibroblasts as key effector cells in myofibroblast differentiation and extracellular matrix deposition, endothelial cells also play a role in the processes of IPF. Endothelial cells can transform into myofibroblasts; therefore, endothelial-mesenchymal transition can be another source of myofibroblasts.

Keywords: E3 ligase; TGF-β; endothelial cell; epithelial mesenchymal transition (EMT); fibroblast; idiopathic pulmonary fibrosis (IPF); ubiquitin proteasome system.

Figure 1

Representative optical microscopy images of fibrotic lungs. Hematoxylin-eosin stain for human idiopathic pulmonary fibrosis (A,B) and bleomycin-treated mouse lungs at day 7 (C), day 21 (D), and day 28 (E). The images of human idiopathic pulmonary fibrosis show usual interstitial pneumonia pattern, architectural destruction, heterogeneous patchy distribution of fibrosis with scarring and honeycomb changes, and scattered fibroblastic foci.

Figure 2

Current concepts of IPF pathogenesis. AKAP 13, A-kinase anchoring protein 13; CTGF, connective tissue growth factor; FGF, fibroblast growth factor; MUC5B, mucin 5B; PDGF, platelet-derived growth factor; TERT, telomerase reverse transcriptase; TNF-α, tumor necrosis factor-α.

Figure 3

Possible modulators of fibrosis via regulating TGF-β signaling and cell proliferation. TGF-β signaling promotes induction of epithelial–mesenchymal transition (EMT) and expression of fibrosis-associated genes via TGF-β-Smad-dependent canonical pathway and non-Smad pathway. In the canonical pathway, TGF-β binds to and activates its receptor complex and promotes phosphorylation of Smad2/3. Then activated Smad2/3 forms a complex with Smad4 and the complex binds to the promoter regions of target genes associated with EMT and fibrosis. Inhibitory Smad such as Smad7 and Smad cofactors to regulate the TGF-β-Smad pathway. MiRNA such as miR-21 inhibits translation of Smad7 as a positive regulator of TGF-β signaling. Several lncRNAs participate in controlling TGF-β-mediated EMT and/or fibrosis. A lncRNA ELIT-1 which is induced by TGF-β-Smad pathway binds to Smad3 to facilitate recruitment to promoters of Smad target genes promoting EMT as a Smad cofactor. Moreover, several E3 ubiquitin ligases are involved in promotion in pulmonary fibrosis. Skp2 which promotes p27 degradation is involved in promotion of EMT and mesenchymal fibroblast proliferation. Fbw7 which participates in TPP1 degradation promotes alveolar epithelial stem cell senescence and pulmonary fibrosis. Abbreviations and details of each molecule are indicated in the text.