4. DISCUSSION
CRSwNP is a complex disease involving various types of cells,
inflammatory mediators, and cytokines, and has a high recurrence
rate.4 However, its pathogenesis is still unclear.
Recent studies have revealed that nasal mucosal barrier damage plays an
important role in CRSwNP. Therefore, studies on mucosal barrier damage
repair may reveal new strategies for the treatment of nasal polyps.
Many studies have suggested that MG53 is involved in various
physiological and pathological processes19, including
acute cell membrane repair,29 lung
injury,25 kidney injury,26 ischemic
protection of cardiac fibroblasts,27 and anti-tissue
fibrosis.29 Thus, it is believed to play an important
role in the process of injury repair. TGF-β1 is a pluripotent cytokine
that promotes the deposition of extracellular matrix (ECM). Studies have
shown that TGF-β1 regulates ECM mainly through epithelial-mesenchymal
transition, thereby regulating tissue remodelling and repair, wound
healing, fibrosis, and tumour invasion.15 Thus, TGF-β1
acts as a key factor in tissue repair and fibrosis, reducing tissue
damage by inhibiting the release of pro-inflammatory mediators. It is
also known to activate myofibroblasts for wound closure, and to cause
abnormal collagen deposition. In this study, we found that MG53
exhibited a dual effect, that is, it not only protected the epithelial
barrier, but also promoted the proliferation of epithelial cells in the
nasal mucosa.
We found that the expression of MG53, TGF-β1, Smad2/3, ZO-1, and Col-a1
in tissues and extracted nasal epithelial cells was higher in the CRSsNP
group and lower in the CRSwNP group compared with the control group.
This indicated that higher amounts of ZO-1 and Col-a1 were present in
CRSsNP, and excessive repair occurred after epithelial barrier injury,
nasal epithelial fibrosis, and consequently, tissue
remodelling.24 The low expression of ZO-1 and Col-a1
in the CRSwNP group resulted in insufficient repair after epithelial
injury, leading to nasal mucosal oedema. MG53 showed increasing and
decreasing trends similar to TGF-β1 and Smad2/3, indicating that there
was a regulatory relationship between the MG53/TGF-β1/Smad pathway and
the nasal epithelial barrier process.
Previous studies have suggested that MG53 has a protective effect in
cell membrane damage,23, 24 but its protective effect
on nasal epithelial repair remains unclear. In our study, nasal
epithelial cells isolated from the CRSwNP group were treated with
Ad-MG53, siRNA, TGF-β1, and TGF-β1 inhibitor, and it was observed that
MG53 inhibited the TGF-β1/Smad pathway, and both MG53 and TGF-β1 had
protective effects on the nasal epithelial barrier. However, they
adopted different pathways to repair the nasal epithelial barrier after
injury; TGF-β1 promoted the expression of ZO-1 and Col-a1 to repair the
nasal epithelial barrier by promoting fibrosis, whereas MG53 inhibited
the TGF-β1/Smad pathway, in turn, inhibiting fibrosis repair, and
promoting epithelial cell proliferation, thus, playing a protective role
in the nasal epithelial barrier.
Our study had various limitations. First, we lacked an animal model of
nasal polyps. Second, TGF-β1 had a wide range of effects, likely caused
by the different concentrations. The concentrations used in our study
were based on previous literature. Therefore, we did not screen for the
concentrations used. Finally, MG53 exerted its protective effect on the
cell membrane in various ways. However, our study only elaborated on its
protective mechanism from the perspective of the epithelial barrier.
Thus, further studies are required to understand the possible mechanism
of MG53.
Our study demonstrated the importance
of repairing the imbalance after nasal epithelial barrier injury in
CRSwNP and CRSsNP, and provided significant cues for the role of MG53 in
inhibiting fibrosis and promoting epithelial hyperplasia. Thus, MG53
might be an important clinical treatment option for nasal polyps.