Chaotic activation of developmental signalling pathways drives idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterised by an important remodelling of lung parenchyma. Current evidence indicates that the disease is triggered by alveolar epithelium activation following chronic lung injury, resulting in alveolar epithelial type 2 cell hyperplasia and bronchiolisation of alveoli. Signals are then delivered to fibroblasts that undergo differentiation into myofibroblasts. These changes in lung architecture require the activation of developmental pathways that are important regulators of cell transformation, growth and migration. Among others, aberrant expression of profibrotic Wnt-β-catenin, transforming growth factor-β and Sonic hedgehog pathways in IPF fibroblasts has been assessed. In the present review, we will discuss the transcriptional integration of these different pathways during IPF as compared with lung early ontogeny. We will challenge the hypothesis that aberrant transcriptional integration of these pathways might be under the control of a chaotic dynamic, meaning that a small change in baseline conditions could be sufficient to trigger fibrosis rather than repair in a chronically injured lung. Finally, we will discuss some potential opportunities for treatment, either by suppressing deleterious mechanisms or by enhancing the expression of pathways involved in lung repair. Whether developmental mechanisms are involved in repair processes induced by stem cell therapy will also be discussed.

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

“…Repetitive injury to AEC2 results in exhaustion of their replicative potential, and the secretion of cytokines and growth factors promotes both the recruitment of immune cells and activation of fibroblasts into myofibroblasts ( Chapman, 2011 ; Wynn, 2011 ). Accumulation of macrophages with a profibrotic phenotype and senescent AEC2 failing to repair alveolar damage ultimately lead to progressive and irreversible lung tissue destruction ( Chilosi et al, 2012 ; Lehmann et al, 2020 ), orchestrated by epithelial–mesenchymal crosstalk and aberrant reactivation of developmental pathways including WNT/β-catenin, Notch, and Sonic Hedgehog ( Carraro et al, 2020 ; Froidure et al, 2020 ).…”

The miR-130a-3p/TGF-βRII Axis Participates in Inhibiting the Differentiation of Fibroblasts Induced by TGF-β1

“…Aberrant transcription of signaling pathways might trigger PF, among which TGF-β1 plays a central role ( Saito et al, 2018a ; Froidure et al, 2020 ). As expected, TGF-β1/Smad signaling pathway proteins (TGF-βRII, SMAD2/3 and p-SMAD2/3) increased with TGF-β1 treatment, which was reversed after BMSC administration ( Figures 2A–C ), and verified at the mRNA level ( Figures 2D–F ).…”

“…Pulmonary fibrosis (PF) is a chronic lung disease, and its incidence has been rising in recent years ( Wu and Xu, 2020 ; Li et al, 2021 ). PF usually affects elderly patients, and radiation and mechanical or chemical stimulation have become the main risk factors associated with PF ( Froidure et al, 2020 ; Jin et al, 2020 ; Yang et al, 2020 ). The main pathological features of PF are alveolar epithelial cell damage, fibroblast proliferation and activation, excessive collagen deposition, and a large accumulation of extracellular matrix ( Sauler et al, 2019 ; Zhi et al, 2020 ).…”

PRMT7 targets of Foxm1 controls alveolar myofibroblast proliferation and differentiation during alveologenesis

“…Later on, in the saccular phase, PDGFRα positive cells migrated to the periphery of the terminal cyst wall to form the secondary crest, and differentiated into mature α-SMA + AMYFs to produce elastin [ 9 ]. Disruption of AMYFs differentiation, proliferation, or migration leads to the failure formation of the secondary septum and arrested alveolarization during lung development [ 10 ], and are found in several pulmonary diseases including emphysema, idiopathic pulmonary fibrosis (IPF), BPD, and chronic obstructive pulmonary disease (COPD) [ 11 ]. Moreover, given that AMYFs are the primary cell types responsible for the accumulation of extracellular matrix (ECM) during fibrotic diseases, targeting AMYFs proliferation and differentiation is an important therapeutic strategy for the treatment of pulmonary diseases [ 12 ].…”