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.