Mechanistic Regulation of Wnt Pathway-Related Progression of Chronic Obstructive Pulmonary Disease Airway Lesions

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic disease associated with inflammation and structural changes in the airways and lungs, resulting from a combination of genetic and environmental factors. This interaction highlights significant genes in early life, particularly those involved in lung development, such as the Wnt signaling pathway. The Wnt signaling pathway plays an important role in cell homeostasis, and its abnormal activation can lead to the occurrence of related diseases such as asthma, COPD, and lung cancer. Due to the fact that the Wnt pathway is mechanically sensitive, abnormal activation of the Wnt pathway by mechanical stress contributes to the progression of chronic diseases. But in the context of COPD, it has received little attention. In this review, we aim to summarize the important current evidence on mechanical stress through the Wnt pathway in airway inflammation and structural changes in COPD and to provide potential targets for COPD treatment strategies.

Keywords: COPD; Wnt signaling pathway; airway remodeling; mechanical signal; β-catenin.

Figure 1

WNT/b-catenin signaling pathway. A simplified scheme showing the major pathways of WNT. In the absence of WNT ligand, glycogen synthase kinase 3 (GSK-3) phosphorylates β-catenin, triggering ubiquitinated proteasomal degradation; Extracellular WNT ligands bind to Frizzled receptor and disrupt complexes [including GSK-3, casein kinase-IA] (CK-LA), axin, and adenomatous polyposis Escherichia coli (APC)] are recruited to the cell membrane side, which saturates the destruction complex and allows the accumulation and translocation of newly formed B-catenin into the nucleus, where it activates the transcription of target genes under the control of T cytokines (TCF).

Figure 2

β-catenin independent signaling. Orange-and-brown labeled components depict planar cell polarity (PCP) and WNT/Ca2+ signaling, respectively. PCP signaling triggers activation of small GTPases such as RhoA and Rac-1, which in turn activates Rho-kinase (ROCK) and Jun-N-terminal kinase (JNK), leading to actin polymerization. This pathway is significantly involved in the regulation of cell polarity, motility, and contraction. The WNT/Ca2+ pathway activates calmodulation-independent kinase II (CamKIl) and protein kinase C (PKC), which in turn activate Ca2+ -sensitive transcription factors, including T-cell activated nuclear factor (NFAT), which regulates transcription of genes that control cell fate and cell migration.In airway smooth muscle cells, Wnt11 activates RhoA in response to TGF-B-induced upregulation of SM-A-actin. ROCK activation is involved in the extracellular matrix. Degree promotes the process of β-catenin nuclear translocation. However, under certain circumstances, JNK activation induces tyrosine phosphorylation of b-catenin, thereby inhibiting its nuclear translocation and thereby inhibiting the canonical WNT signaling pathway.