Resveratrol Attenuates Airway Remodelling By Inhibiting TGF-?1/Smad Signalling Passway On Chronic Experimental Asthma

Objective:To investigate the effects of resveratrol on airway inflammation and remodelling in a murine model of chronic asthma and its possible mechanisms.Methods:32female BALB/c mice are randomly divided into four groups. They are control group, OVA group, resveratrol group and budesonide group. Every group contained8mice. Ovalbumin (OVA)-sensitized mice were chronically challenged with aerosolized5%OVA for30min/day,3days/week up to day55. Mice in the resveratrol group were intragastrically administered with resveratrol (30mg/kg) daily up to day55. Mice in the budesonide group were exposed to an aerosol of budesonide daily during the period of OVA challenge. The sections were stained. with either hematoxylin&eosin to assess the inflammatory cell infiltrates, periodic acid schiff (PAS) to quantify airway global cells and Masson's trichrome to determine collagen deposition in the lungs. Total collagen content of the lung was determined by hydroxyproline assay. Interleukin (IL)-4and IL-13levels in bronchoalveolar lavage fluid (BALF), and total immunoglobulin E (IgE) levels in serum were measured by ELISA.The expression of ?-SMA and TGF-?1in lungs were evaluated by immunohistochemistry. The protein expression of TGF-?1?p-Smad3?Smad7were determined by western blot. The mRNA of TGF-?1?fibronectin and collagen-1were measured by real time PCR. Results:The number of eosinophils and total inflammatory cells in BALF in the OVA group increased significantly compared with the control group (P<0.01). Treatment with resveratrol or budesonide significantly decreased the number of eosinophils and total inflammatory cells in BALF (P<0.05). There were no significant differences in the number of eosinophils and total inflammatory cells in BALF between the resveratrol group and budesonide group (P>0.05). The levels of the Th2cytokines IL-4and IL-13in BALF and total serum IgE were significantly increased in OVA-sensitized/challenged mice comapred with the control group (P<0.01). Daily administration of resveratrol or budesonide reduced the levels of these Th2cytokine in BALF and total serum IgE compared with the OVA group (P<0.05). There were no significant differences in the levels of BALF IL-4and IL-13and total serum IgE between the resveratrol group and budesonide group(P>0.05). A significant increase in the number of PAS-positive epithelial cells was found in the OVA group compared with the negative control group (P<0.01). Treatment with resveratrol or budesonide reduced the number of PAS-positive cells (P<0.05). The mean area of Masson's trichrome staining(collagen deposition) in the OVA group was significantly enhanced compared with the negative control group (P<0.01). Administration of resveratrol or budesonide caused a marked reduction in collagen deposition compared with the OVA group (P<0.05). Total lung hydroxyproline content in the OVA group was significantly greater than that in the control group (P<0.01). In contrast, treatment with resveratrol or budesonide significantly reduced total lung hydroxyproline content compared with the OVA group (P<0.05). The area of the a-SMA-stained smooth muscle layer in OVA-sensitized and challenged mice was significantly greater than that in the control group (P<0.01). Administration of resveratrol or budesonide decreased the a-SMA immunostained area compared with the OVA group (P<0.05). The mRNA levels of TGF-?1?fibronectin and collagen-1in the lungs in the OVA group increased significantly compared with that in the control group(P<0.05). Treatment with resveratrol or budesonide decreased the mRNA levels of TGF-?1?fibronectin and collagen-1compared with that in the OVA group(P<0.05). The protein levels of TGF-?1and p-Smad3in the lung in the OVA group was significantly enhanced compared with the negative control group (P<0.01), administration of resveratrol or budesonide decreased the TGF-?1and p-Smad3protein levels compared with the OVA group (P<0.05), whereas the total of Smad3were not affected (p>0.05). In contrast, Smad7was markedly up-regulated in mice treated with resveratrol or budesonide compared with the OVA group(P<0.05). There was no significant differences of TGF-?1?p-Smad3and Smad7in mice treated with resveratrol or budesonide. Conclusion:Resveratrol can suppress the development of airway inflammation and airway remodelling via regulating the TGF-?1/Smad signaling passway in a murine model of chronic asthma.