AUTHOR=Hachim Mahmood Yaseen , Elemam Noha Mousaad , Ramakrishnan Rakhee K. , Bajbouj Khuloud , Olivenstein Ronald , Hachim Ibrahim Yaseen , Al Heialy Saba , Hamid Qutayba , Busch Hauke , Hamoudi Rifat 

TITLE=Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.641404

DOI=10.3389/fcell.2021.641404

ISSN=2296-634X

ABSTRACT=Both canonical and noncanonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target.Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. 
Here we explored the changes in Wnt signaling associated with Asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based on in silico analysis and followed by in vitro validation. In summary, the in-silico analysis showed that bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. Th2-high phenotype is associated with upregulated Wnt negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling members enrichment. Most of these genes are the regulator of healthy lung development early in life and, if disturbed, can make people susceptible to develop asthma early in life and prone to develop severe phenotype. Most of Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which put cells in stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is dependent on Wnt signaling also. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO treated cells. In asthmatic fibroblasts, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged beside other pathways that might be nonfunctional.