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.