The Wnt7b/β-catenin signaling pathway is involved in the protective action of calcitonin gene-related peptide on hyperoxia-induced lung injury in premature rats

Abstract

BackgroundCalcitonin gene-related peptide (CGRP) can protect against hyperoxia-induced lung injury, making the upregulation of CGRP a potential therapeutic approach for this type of injury. However, the effects of CGRP on the Wnt7b/β-catenin signaling pathway are unclear. In this study, we investigated the roles of CGRP and the Wnt7b/β-catenin signaling pathway in hyperoxia-induced lung injury.MethodsPremature Sprague Dawley (SD) rats were exposed to 21, 40, 60 and 95% oxygen for 3, 7 and 14 days. The animals’ body weights, survival rates and endogenous CGRP levels were measured. Lung samples were harvested for histological analyses and measurements of malondialdehyde (MDA) concentration and total antioxidant capacity (TAOC). We also assessed the MDA concentration and TAOC in the lung tissues after administration of 200 nmol/kg CGRP8–37 (a CGRP antagonist). Finally, alveolar epithelial type II (AEC II) cells were isolated from premature rats, exposed to 21 or 95% oxygen for 3, 7 and 14 days, and treated with 10− 8 mol/l exogenous CGRP. The protein expressions of Wnt7b and β-catenin were assessed using western blotting, and TCF and c-myc mRNA expressions were assessed using qPCR.ResultsRats exposed to 60 and 95% oxygen had significantly lower body weights and survival rates than the 21 and 40% groups, and the decrease was time dependent. Endogenous CGRP was elevated in the lung tissues of premature rats exposed to 95% oxygen. CGRP8–37 induced apparent inflammation in the lung tissue and alveolar structural remodeling. In addition, the expression levels of Wnt7b and β-catenin were markedly increased after exposure for 3 days. They peaked at 7 days, then declined at 14 days. The levels of TCF/c-myc in AEC II cells increased significantly after CGRP treatment when compared with cells that had only undergone hyperoxia.ConclusionsCGRP protected against hyperoxia-induced lung injury in premature rats. This process involves the Wnt7b/β-catenin signaling pathway.

Analysis of Wnt7B and BMP4 expression patterns in congenital pulmonary airway malformation

“…32 It has been previously reported that Wnt7B is highly expressed in developing airway epithelial cells and is required for normal lung mesenchymal cell proliferation as a mediator of epithelial-mesenchymal interactions; inactivation of Wnt7B leads to inhibition of epithelial proliferation and stromal cell and bronchial branching disorders. 33 These previous observations are in accord with the theory that Wnt7B mediates lung branching The ligands and receptors of BMP signaling are highly expressed in the distal airways, and previous studies in which BMP4 was shown to be overexpressed in lung endoderm suggested that this factor plays an important role in lung morphogenesis. 34,35 In addition, BMP4 does not signal epithelial cells to adopt a distal fate but may regulate the expansion of proximal epithelial cells in the lung.…”

“…In the normal human lung development process, Wnt7B was dramatically upregulated in the respiratory airways from 7 to 17 weeks (pseudoglandular stage) but was barely detectable at 21 weeks 32 . It has been previously reported that Wnt7B is highly expressed in developing airway epithelial cells and is required for normal lung mesenchymal cell proliferation as a mediator of epithelial‐mesenchymal interactions; inactivation of Wnt7B leads to inhibition of epithelial proliferation and stromal cell and bronchial branching disorders 33 . These previous observations are in accord with the theory that Wnt7B mediates lung branching morphogenesis through the epithelial‐mesenchymal transition signaling pathway.…”

Intranasal Calcitonin Gene-Related Peptide Protects Against Focal Cerebral Ischemic Injury in Rats Through the Wnt/β-Catenin Pathway

“…Tapia-Rojas et al highlighted the importance of Wnt/β-catenin signaling dysfunction in the onset of Alzheimer’s disease and proposed that the loss of canonical Wnt signaling was a triggering factor of Alzheimer’s disease [23]. Recently, Wang et al reported that CGRP protected against hyperoxia-induced lung injury in premature rats through the Wnt7b/β-catenin signaling pathway [24]. We hypothesized if the neuroprotective role of CGRP might be correlated with the Wnt/β-catenin pathway.…”

CGRP induces myofibroblast differentiation and the production of extracellular matrix in MRC5s via autocrine and paracrine signalings

“…[ 38 ] In another study, it was found that CGRP protected the rat lungs from hyperoxia‐induced oxidative damage throughWnt7b/β‐catenin signaling. [ 39 ] A study performed on human osteoblasts revealed the relation between CGRP and Wnt/β‐catenin signaling‐mediated cell apoptosis. It was found that β‐catenin levels increased in the first 60 min after CGRP administration to primary human osteoblast culture.…”