The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A

Abstract

Introduction: Chronic inflammatory lung diseases are a common cause of suffering and death. Chronic obstructive pulmonary disease (COPD) is the reason for 6% of all deaths worldwide. A total of 262 million people are affected by asthma and 461,000 people died in 2019. Idiopathic pulmonary fibrosis (IPF) is diagnosed in 3 million people worldwide, with an onset over the age of 50 with a mean survival of only 24-30 months. These three diseases have in common that remodeling of the lung tissue takes place, which is responsible for an irreversible decline of lung function. Pathological lung remodeling is mediated by a complex interaction of different, often misguided, repair processes regulated by a variety of mediators. One group of these, as has recently become known, are the Wnt ligands. In addition to their well-characterized role in embryogenesis, this group of glycoproteins is also involved in immunological and structural repair processes. Depending on the combination of the Wnt ligand with its receptors and co-receptors, canonical and noncanonical signaling cascades can be induced. Wnt5A is a mediator that is described mainly in noncanonical Wnt signaling and has been shown to play an important role in different inflammatory diseases and malignancies.

Objectives: In this review, we summarize the literature available regarding the role of Wnt5A as an immune modulator and its role in the development of asthma, COPD and IPF. We will focus specifically on what is known about Wnt5A concerning its role in the remodeling processes involved in the chronification of the diseases.

Conclusion: Wnt5A has been shown to be involved in all three inflammatory lung diseases. Since the ligand affects both structural and immunological processes, it is an interesting target for the treatment of lung diseases whose pathology involves a restructuring of the lung tissue triggered in part by an inflammatory immune response.

Keywords: Airway remodeling; Asthma; Chronic obstructive pulmonary disease; Idiopathic pulmonary fibrosis; Member 5A; Wingless-Type MMTV Integration Site Family.

Fig. 1

Role of fibroblasts in tissue remodeling (TGF-Beta transforming growth factor-Beta, Alpha-SMA alpha smooth muscle cells, MMP matrix metalloproteinase, TIMP tissue inhibitor of metalloproteinase, ECM extracellular matrix, LOX lysyl oxidase-like protein, TG transglutaminase)

Fig. 2

Wnt5A in asthma. Visual summary of the major points described in the text. PBMC peripheral blood mononuclear cells, BEC bronchial epithelial cells, SMC airway smooth muscle cells, ECM extracellular matrix, TGM2 transglutaminase 2 and Col1A1 alpha-1 type 1 collagen

Fig. 3

Role of Wnt5A in COPD. Fzd4 Frizzled 4, AEC alveolar epithelial cells

Fig. 4

Wnt5A contributes to IPF. SMC smooth muscle cells