Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling

Abstract

Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/β-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/β-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/β-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling.

Targeted inhibition of β-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-β1

“…Therefore, in our study, Wistar rats with OVA were challenged to construct chronic asthma model, based on the experimental method. The signaling protein β-catenin has an important role in lung development, injury, and repair whereas the aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling [18][19]. Thus, β-catenin is a therapeutic target in airway remodeling of asthma.…”

“…By comparison, broblasts can contribute to airway remodeling via accumulating in subepithelial regions, differentiating into myo broblasts, and secreting ECM components [33]. As demonstrated by research, TGF-β 1 can trigger EMT by affecting the release, stabilization, and activation of β-catenin, and promoting the transcription of its target gene [19]. Moreover, TGF-β 1 can stimulate broblast proliferation and differentiation into myo broblasts, which have secretory and contractile phenotypes and express α-SMA [34].…”

Tenascin-C inactivation impacts lung structure and function beyond lung development

“…The effect of down-regulation of α-SMA + cells following TNC inactivation could therefore constitute an interesting approach in the prevention or treatment of obstructive pulmonary diseases with thickened ASM layer or heterogeneous ventilation. Indeed, the same Wnt/TNC/PDGFR pathway regulating SMC formation and differentiation during lung development was recently shown to recur in airway remodeling in chronic asthma 52,53 .…”

Retinoic Acid: A Key Regulator of Lung Development

“…The crosstalk between the epithelial and mesenchymal compartment is conveyed by several diffusible signals from multiple signaling pathways including Sonic Hedgehog (SHH) [32], Wingless-related Integration Site (WNT) [33], Transforming Growth Factor β (TGFβ), Bone Morphogenetic Protein (BMP) [34], Fibroblast Growth Factor (FGF) [35], Hippo [36], and Retinoic Acid [4], just to name a few. In the next sections, we will dissect the role of RA throughout the five lung developmental phases, namely, embryonic, pseudoglandular, canalicular, saccular, and alveolar ( Figure 2), and also in lung vascular development.…”