Osthole ameliorates cigarette smoke-induced epithelial-to-mesenchymal transition via PI3K/Akt/NF-κB pathway in chronic rhinosinusitis with nasal polyps.

Abstract

Introduction: Osthole, a naturally occurring coumarin derivative, has been isolated from the traditional Chinese medicinal herb Cnidium monnieri. This compound exhibits a range of pharmacological properties, including anticancer, antioxidant, anti-inflammatory, and immunomodulatory effects. The objective of this study was to investigate the role of osthole in tissue remodeling in chronic rhinosinusitis with nasal polyp (CRSwNP).

Methods: The effects of osthole on nasal polyp (NP) formation were examined within a mouse model of NPs induced by cigarette smoke (CS). The detection of polypoid changes and goblet cell metaplasia was achieved through the use of haematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining, respectively. The levels of TGF-β1, matrix metalloproteinases 2, 7, 9, and 12 (MMP2, MMP7, MMP9, MMP12), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1) in nasal lavage fluid were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was employed to ascertain the expression of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, ZO-1, α-SMA and vimentin), as well as the activity of the PI3K/AKT/NF-κB pathway. The expression of E-cadherin in nasal epithelium was determined through immunohistochemistry.

Results: In the OVA+SEB or CS-exposed NP mouse model, osthole was observed to reduce the incidence of polypoid changes and goblet cells, while simultaneously increasing the expression of E-cadherin in the epithelium when compared to the CS-treated group. After treatment with osthole, the levels of TGF-β1, MMP2, MMP7, MMP9 and MMP12 in nasal lavage fluid were observed to decrease, while the levels of TIMP-1 were found to increase. In vitro, cigarette smoke extract (CSE) was observed to down-regulate the expression of E-cadherin and ZO-1, while simultaneously up-regulating the expression of α-SMA and vimentin. Moreover, osthole up-regulated the expression of E-cadherin and ZO-1 while down-regulating the expression of α-SMA and vimentin. This effect of osthole was reversed by PI3K/AKT/NF-κB pathway agonists.

Conclusion: Osthole attenuates CS exposure-induced EMT via the PI3K/AKT/NF-κB pathway, providing a theoretical and experimental basis for its clinical application in the treatment of CRSwNP.