Reactivated developmental pathways, transcription factors and senescence in idiopathic pulmonary fibrosis (IPF)

Role in lung developmentRole in normal lung regeneration after injuryProposed role in IPF
Developmental pathways
 Canonical Wnt/β-cateninRegulates cell proliferation, differentiation, cell fate specification and stem cell renewal. Participates in branching morphogenesis, regional specialisation of the epithelium and mesenchyme, and the establishment of progenitor cell pools [35–38].Wnt7b is expressed by surviving ciliated epithelial cells and induces the expression of FGF10 in progenitor cells from the mesenchyme, which is essential for proliferation and differentiation during epithelial repair after lung injury [32]. ERG, an ETS transcription factor, is an essential regulator of angiogenesis and vascular stability through Wnt signalling [40].Induces epithelial cell proliferation, secretion of profibrotic mediators, epithelial-to-mesenchymal transition, fibroblast migration and myofibroblast differentiation [14–16].
 Non-canonical Wnt signalling (e.g. Wnt5a) that includes Wnt/PCP (planar cell polarity) and Wnt/Ca2+Wnt5a regulates epithelial–mesenchymal interactions, playing an important role in lung distal morphogenesis [39].Increases fibroblast proliferation and resistance to apoptosis [18].
 Sonic hedgehog (SHH)Indispensable for embryonic lung formation, regulates branching morphogenesis and mesenchymal proliferation affecting proliferation and differentiation of lung mesenchyme [35–38].SHH ligand and GLI1, a transcriptional target of the signalling pathway, are markedly expressed in the epithelial compartment 72 h after naphthalene injury [33].It increases proliferation, migration, extracellular matrix production, and survival of fibroblasts. Smoothened, the obligatory signal transducer of the pathway, is required for TGF-β1-induced myofibroblastic differentiation [20, 21].
 Fibroblast growth factor (FGF)9Regulates lung mesenchymal development. FGF9 signalling from the epithelium and reciprocal FGF10 signalling from the mesenchyme coordinate to regulate epithelial airway branching and organ size during lung embryogenesis [35–38].Unclear. It may induce an antifibrotic phenotype in fibroblasts. In collaboration with FGF10 and other factors it may facilitate re-epithelialisation [29].It promotes fibroblast migration and survival, but reduces fibroblast to myofibroblast differentiation [29].
Transcription factors
 Grainyhead-like 2Master regulator of epithelial morphogenesis and integrity including apical–basal polarity, intercellular adhesion and barrier function as well as lineage choice and differentiation of progenitor populations [21, 41].May contribute to the epithelial–mesenchymal plasticity. It maintains telomerase activity in fibroblasts? [22, 23].
 Wilms tumour-1Zinc finger transcription factor that regulates many functional properties of the developing mesothelium [42].May increase the fibroblast/myofibroblast population inducing mesothelial-to-mesenchymal transition [25–27].
 Forkhead box F1Is expressed at highest levels in the subepithelial lung mesenchyme between the distal bulbous part of the bud and proximal tubular part. It plays an important role in epithelium–mesenchyme signalling, as a downstream target of the SHH pathway. It is essential for the migration of mesenchymal cells and directly induces integrin-β3 expression in mouse embryonic lungs, and regulates expression of VEGF signalling in endothelial cells [43].Attenuates the profibrotic phenotype in normal fibroblasts, but this effect is dampened in IPF fibroblasts [28].
SenescenceIt is a programmed developmental mechanism found throughout the embryo, including critical signalling centres in embryonic patterning. It is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodelling [44, 45].Unknown; it plays an important role against cancer [46].Senescence-associated secretory phenotype from the epithelial cells may contribute to the abnormal expression of the numerous profibrotic factors secreted by these cells [2, 5, 47, 48]. It may contribute to the apoptosis-resistance of fibroblasts [49].
Transforming growth factor (TGF)-βIn human embryonic stem cells, TGF-β signalling and Smad2/3 activation are involved in self-renewal and pluripotency. TGF-β is a key player for epithelial–mesenchymal interactions during lung morphogenesis. It regulates alveolar type 1 cell spreading and adhesion during lung sacculation [35, 50, 51].It participates as an anti-inflammatory mediator. It has an immune suppressor effect by influencing the development, differentiation, tolerance induction and homeostasis of immune cells [52].Probably the strongest profibrotic factor. It cross-talks with several developmental pathways signalling at multiple levels both during development and contributing to the aberrant integration of profibrotic factors in IPF [2].
  • VEGF: vascular endothelial growth factor; PI3K: phosphoinositide 3-kinase.