Perspectives on Wnt Signal Pathway in the Pathogenesis and Therapeutics of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with progressive airflow limitation and functional decline. The pathogenic mechanisms for this disease include oxidative stress, inflammatory responses, disturbed protease/antiprotease equilibrium, apoptosis/proliferation imbalance, senescence, autophagy, metabolic reprogramming, and mitochondrial dysfunction. The Wnt signaling pathway is an evolutionarily conserved signaling pathway that is abnormal in COPD, including chronic bronchitis and pulmonary emphysema. Furthermore, Wnt signaling has been shown to modulate aforementioned cellular processes involved in COPD. From this perspective, we provide an updated understanding of the crosstalk between Wnt signal and these cellular processes, and highlight the crucial role of the Wnt signal during the development of COPD. We also discuss the potential for targeting the Wnt signal in future translational and pharmacological therapeutics aimed at prevention and treatment of this disease.

A Positive Feed Forward Loop between Wnt/β-Catenin and NOX4 Promotes Silicon Dioxide-Induced Epithelial-Mesenchymal Transition of Lung Epithelial Cells

“…However, accumulating evidences have shown that Wnt has been implicated in many types of pulmonary diseases, and a dysregulated Wnt signaling in mature lungs was recognized as a driver that leads to excessive cell proliferation and improper cell differentiation for fibrotic repair [ 36 , 37 ]. Indeed, a reactivated Wnt was identified as a key contributor in the initiation and development of hyperproliferative chronic pulmonary diseases [ 9 , 12 ], such as idiopathic pulmonary fibrosis (IPF) [ 11 , 38 ], asthma [ 39 ], and COPD [ 8 , 11 , 34 , 40 ]. With respect to silicosis, both β -catenin-mediated canonical signaling and β -catenin-independent noncanonical signaling were altered in human airway epithelial cells upon silica stimulation; the Wnt inhibitor SFRP1 and noncanonical ligand Wnt5a were downregulated, while another Wnt inhibitor DKK1 was upregulated [ 13 ], despite the fact that the canonical Wnt/ β -catenin signaling was reactivated in silicosis lungs [ 14 , 15 ].…”

“…Similar to that demonstrated in other chronic lung diseases, the pathogenesis of silicosis is controlled by interactions between various cellular signaling pathways [ 7 – 10 ]. Among them, the wingless-type MMTV-integration site (Wnt)/ β -catenin signaling, a well-known critical cellular signaling pathway in embryonic development and tissue homeostasis, is reactivated in many chronic pulmonary diseases, including silicosis [ 8 , 9 , 11 – 13 ]. A blocking of Wnt/ β -catenin signaling alleviated the lung inflammation and fibrosis in silica-induced mouse and rat silicosis models [ 14 – 16 ].…”

DNA methylation perturbations may link altered development and aging in the lung

“…Age associated epigenetic variation may additionally reveal genes further disrupted in age associated lung diseases such as COPD. In our fetal lung aDMPs, we found previously discussed differentially methylated age-associations identified in fetal brain tissue [ 13 ] including the Wnt antagonist SFRP1 known to be differentially methylated in adults with asthma [ 41 ] and previously associated with emphysema [ 42 ], nuclear receptor gene NR4A2 crucial for neurogenesis and SHANK2 implicated in neurodevelopmental disorders such as autism and severe asthma [ 13 , 43 ]. ELOVL2 is a consistently identified biomarker for aging [ 12 ] further supported by our finding of association of the age-related ELOVL2 gene and the rapid hypermethylation of its promoter cg16867657 [ 25 , 44 ].…”

Analysis of the polarization states of the alveolar macrophages in chronic obstructive pulmonary disease samples based on miRNA-mRNA network signatures

“…The typical phenotype is the increase of monocytes, lymphocytes, and neutrophils, leading to changes in lung airways and alveoli (3,4). The pathogenesis of COPD includes oxidative stress, inflammation, protease/ antiprotease disorders, apoptosis/proliferation imbalance, aging, autophagy, metabolic disorders, and mitochondrial dysfunction (5,6). Timely treatment can improve the deterioration of the condition, but there is no cure to date.…”