1. INTRODUCTION
Chronic rhinosinusitis (CRS) is a common disease, having 8% prevalence worldwide, and can occur with (CRSwNP) or without (CRSsNP) nasal polyps.1, 2 CRS is usually treated via anti-inflammatory drugs and nasal endoscopic surgery. Compared with CRSsNP, CRSwNP has more severe symptoms, such as nasal congestion, anosmia, and headache, and has a higher recurrence rate, with a two-year recurrence rate of 55.3%.3However, the pathogenesis of nasal polyps is still unclear. Recent studies have revealed the importance of the nasal mucosal barrier in CRS.4, 5
The nasal mucosal barrier is the first line of defence against harmful foreign substances, forming a physical barrier against allergens, pathogens, and irritants. This epithelial barrier is mainly composed of tight junctions (TJs), the topmost intercellular junction complex between adjacent epithelial cells.6, 7 Abnormal TJs prevent the formation of physical barriers, and increase the vulnerability of the submucosal area to foreign molecules.8 Patients with CRS have damaged nasal epithelial cells, with decreased cilia count and malfunction, as well as impaired mucosal barrier function, thus, providing the basis for increased permeability, allowing the entry of harmful substances into the sub-epithelial layer. This results in an abnormal immune response in the mucosa, leading to tissue damage, mucosal inflammation, and tissue remodelling changes caused by chronic inflammation.9, 10
Zonula occludens (ZO) is a cytoplasmic adhesion protein belonging to the class of membrane-associated guanosine kinases, which contains multiple domains and binds to other TJs proteins. It is involved in the maintenance of the epithelial barrier and the regulation of barrier functions, as well as in distinct cellular processes, such as signal transduction, cell proliferation and differentiation, immune regulation, cancer cell metastasis, and maintenance of epithelial polarity. There are three subtypes of ZO, viz. ZO-1, ZO-2, and ZO-3, of which ZO-1 is the most characteristic.11, 12
Transforming growth factor (TGF)-β1 is associated with tissue remodelling, post-injury repair, wound healing, fibrosis, and tumour invasion. These biological effects are mainly exerted through classical and non-classical Smad-dependent pathways.13, 14Studies have shown that in terms of tissue remodelling, CRSwNP shows reduced TGF-β1 and collagen expression, along with mesenchymal oedema.15, 16 Additionally, TGF-β1 regulates cell aggregation, elevates the expression of tightly connected ZO-1, and accelerates wound repair, suggesting its vital role in mucosal epithelial injury and repair, and regulation of ZO-1.17, 18
MG53, a new muscle-specific triplex motif protein (TRIM72), is considered as a “band-aid” in the process of damage repair.19, 20 MG53 is an intracellular protein that is secreted into systemic circulation in response to physiological activities, and damage to skeletal muscles or the myocardium.21, 22 Intravenous administration of recombinant human MG53 (rhMG53) has been reported to repair membrane damage in muscle and non-muscle cells,23, 24 as well as improve the association with muscular dystrophy, myocardial infarction, acute lung injury, and acute kidney injury.25-27 Moreover, studies on mice have also reported that treatment with recombinant human MG53 (rhMG53) protein accelerated corneal wound healing in rodents, inhibited wound fibrosis, and decreased TGF-β1 secretion.24, 28, 29
There is a scarcity of reports addressing the role of MG53 in the nasal mucosal barrier, and thus, the mechanism of nasal mucosal barrier regulation is unclear. This study aimed to explore the role of MG53 in mucosal epithelial repair in CRS, especially the modulating role of the TGF-β1/Smad pathway and fibrosis in CRSwNP. Further studies on the role of MG53 in epithelial barrier may provide an effective way to prevent and treat nasal polyps.