Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Hindawi Mediators of Inflammation Volume 2017, Article ID 3520581, 16 pages https://doi.org/10.1155/2017/3520581 Review Article Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis Juan Shi,1 Feng Li,2 Meihui Luo,1 Jun Wei,1,2 and Xiaoming Liu1,2 1 2 Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan 750004, China Institute of Human Stem Cell Research, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China Correspondence should be addressed to Xiaoming Liu; Received 28 December 2016; Revised 29 March 2017; Accepted 12 April 2017; Published 15 May 2017 Academic Editor: Teresa Zelante Copyright © 2017 Juan Shi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases. 1. Introduction Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two severe, chronic pulmonary diseases with distinct clinical and pathological features. Clinicopathologically, COPD is characterized by a progressive and poorly reversible airflow limitation caused by a concurrence of airway inflammations and emphysema, while IPF features an impaired diffusion capacity with a restrictive pattern of lung volume abnormality [1, 2]. While therapeutic interventions are available for ameliorating manifestations of COPD and IPF, there is no curative option currently available, partially owing to the largely unknown pathogenesis of these devastating disorders. Mechanistically, many signaling pathways are involved in the pathogenesis of COPD and IPF. Among them, the transforming growth factor beta (TGF-β) signaling is one of the most studied pathways. Of great interest, developmental signaling pathways, such as wingless-type MMTV integration site (Wnt) pathways, have recently gained increased attention in the onset and progression of chronic pulmonary diseases, particularly in asthma, COPD, and IPF. In this respect, dysregulated Wnt signaling has been implicated in lung remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema [3]. The Wnt pathways are developmental signaling pathways that play pivotal roles in cell fate specification, cell migration and polarity, organogenesis, stem cell self-renewal, and tissue homeostasis under a physiological condition and tissue repair following injuries [4]. With respect to the lung, the expression of various Wnt ligands, including Wnt2, Wnt3A, Wnt5A, Wnt5B, Wnt7B, Wnt 10A, Wnt11, and 2 Wnt13, has been detected in both developing and adult lung [5]. In developing lung, Wnt signaling exerts functions in branching morphogenesis and airway formation [6, 7]. In mature lungs, Wnt signaling is often reactivated during injury repair and tissue regeneration. Moreover, accumulating evidence has demonstrated that dysregulated Wnt signaling is a key contributor to pathogenesis of hyperproliferative lung diseases such as COPD and IPF [3, 7–9]. Clinically, activation of Wnt/β-catenin signaling, accompanied with an increased expression of its target genes (i.e., Cyclin D1 and MMP-7), was observed in airways of patients with IPF [10, 11]. In patients with emphysema, repressed Wnt/ β-catenin signaling activity and reduced expression of its target genes were reported [12, 13]. Interestingly, a reactivation of this signaling led an attenuation of experimental emphysema in vivo [14]. The distinct roles of Wnt/β-catenin in the onset and progression between IPF and COPD suggest the complicity of roles of this signaling in chronic pulmonary diseases. An in-depth understanding of the mechanisms underpinning Wnt signaling-regulated pathogenesis is therefore important for prevention and management of these incurable diseases. In this review article, we attempt to scrutinize recent findings in pathogenic roles of Wnt signaling in COPD and IPF, with a main focus on molecular mechanisms by which the Wnt signaling regulates pathogenesis of these disorders and the potential of this signaling as therapeutic targets for disease treatments. 2. Wnt Signaling Pathways To date, 19 gene encoding distinct Wnt protein ligands have been identified in humans [15]. In the presence of Wnt ligand, the Wnt protein first binds to a seven-transmembranespanning frizzled (FZD) receptor that may also complex with coreceptors such as the low-density lipoprotein-related receptor (LRP) 5 or 6 [15]. Based on the dependence of Wnt signaling effector, β-catenin, Wnt signaling pathways can be further characterized by a “canonical pathway” and several “noncanonical pathways.” The canonical Wnt pathway is also known as the “Wnt/β-catenin pathway,” and the noncanonical pathways include the planer cell polarity (PCP), c-Jun N-terminal protein kinases (JNK), protein kinase C/calcium (PCK/Ca2+), receptor-like tyrosine kinase (RYK), and receptor tyrosine kinase-like orphan receptor (Ror) pathways [4, 15, 16]. Among these, the Wnt/β-catenin signaling pathway is the most investigated and best characterized. The Wnt/β-catenin pathway is characterized by Wnt binding to its coreceptor complex (that constituted by the LRP5 or LRP6) and to a (...truncated)