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.

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

“…CTGF is secreted and activated under stimulation of TGF-β. CTGF mediates lung matrix deposition and fibroblast differentiation by activating downstream MAP kinase pathway ( Duncan et al, 1999 ; Inui et al, 2021 ). In addition, CXCL12 can also induce the expression of CTGF in human lung fibroblasts by activating the MEKK1/JNK signaling pathway ( Lin et al, 2018 ).…”

Identification and functional analysis of a three-miRNA ceRNA network in hypertrophic scars

“…By means of qRT-PCR, we verified the negative correlation between the three miRNAs and three ubiquitination-related genes (CBL, SMURF2, and USP4), which are key components of the ubiquitin–proteasome system and have been shown to engage in the ubiquitination and degradation of some pivotal genes implicated in HTS [ 23 , 24 ]. Consistent with these findings, miR-422a was reported to directly target SKP2 [ 25 ], which is an E3 ubiquitin ligase and was confirmed to promote fibroblast proliferation in pulmonary fibrosis through via ubiquitin–proteasome pathway [ 26 ]. In addition, miR-2116-3p was shown to interact with and inhibit PIWIL1 [ 27 ], and silencing of PIWIL1 was reported to upregulate FBXW7 [ 28 ], which is a component of E3 ubiquitin-protein ligase complex and was observed to induce expression of fibrotic genes including fibronectin during pulmonary fibrosis [ 29 ].…”

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

“…The mechanisms of fibrosis are highly diverse, complex, redundant, and organ-specific, yet there are numerous unifying features across organ- and tissue-specific fibroses. In relevance to pulmonary fibrosis, these mechanisms include, but are not limited to, activation of transforming growth factor-β (TGF-β) ( 133 , 134 ), changes in the levels of other cytokines regulating both inflammation and fibrosis ( 135 – 142 ), oxidative stress ( 143 , 144 ), coagulation disturbances ( 145 , 146 ), changes in biomechanical forces ( 147 , 148 ), cellular senescence ( 149 – 155 ), defective autophagy ( 156 , 157 ), and dysregulated epithelial cell – fibroblast crosstalk ( 158 – 161 ).…”