The Effect Of The Liver-X-Receptors On Airway Inflammation, Airway Hyperresponsiveness And Remodeling In A Murine Model Of Chronic Asthma

Objective:To observe the influence of The Liver-X-Receptors on airway inflammation, airway hyperresponsiveness and remodeling in a murine model of chronic asthma. Methods:Female BALB/c mice were randomly divided into control group, OVA group, Liver-X-Receptors group and dexamethasone group. OVA-sensitized mice were chronically challenged with aerosolized1%OVA for30min/day,3days/week for8weeks. Mice in Liver-X-Receptors group, were administered with traperitoneal injection of T0901317(12.5,25,50mg/kg)2hours before every challenge. Mice in the dexamethasone group were administered with traperitoneal injection of dexamethasone(lmg/kg) daily2hours before every challenge.. Airway responsiveness to Mch (methacholine) was measured with AniRes2005animal lung function analysis systems24hours after the last 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. IL-4, IL-13, TGF-β1in BALF.MMP-9in the lung tissue and total IgE levels in serum were measured by ELISA. The expression of a-SMA in lungs was evaluated by immunohistochemistry. Results:There were no significant differences in baseline airway resistance among the four groups (P>0.05). The airway resistance generated by administration of Mch at doses from12.5to25mg/kg increased significantly in the OVA group compared with the control group (P<0.05). Treatment with The Liver-X-Receptors or dexamethasone led to sharp decrease in airway resistance compared with the OVA group (P<0.05).There were no significant differences between the Liver-X-Receptors and dexamethasone groups (P>0.05). Mice in OVA group displayed severe infiltration of inflammatory cells around the respiratory tract. The numbers of eosinophils and total inflammatory cells in BALF in the OVA group increased significantly compared with the control group (P<0.05). Treatment with dexamethasone resulted in significant reduction of inflammatory cells (P<0.05).There were no significant differences in the numbers of eosinophils and total inflammatory cells in BALF between the Liver-X-Receptors group and OVA group.(P>0.05). The levels of the Th2cytokines in BALF and total serum IgE were significantly increased in OVA group compared with the control group (P<0.05).Treatment with the Liver-X-Receptors or dexamethasone significantly decreased the number of the total serum IgE (P<0.05)..There were no significant differences of the levels of the Th2cytokines in BALF between the Liver-X-Receptors group and OVA group.(P>0.05). A significant increase in the number of PAS-positive epithelial cells was found in the OVA group compared with the control group (P<0.05). Treatment with The Liver-X-Receptors (50mg/kg) or dexamethasone reduced the number of PAS-positive cells (P<0.05). The mean area of Masson’s trichrome staining in the OVA group was significantly enhanced compared with the control group (P<0.05). Administration of The Liver-X-Receptors or dexamethasone 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<0.05). In contrast, treatment with The Liver-X-Receptors (50mg/kg) or dexamethasone significantly reduced total lung hydroxyproline content compared with the OVA group (P<0.05). The levels of TGF-β1in the BALF and the MMP-9in the lung tissue in the OVA group was significantly enhanced compared with the negative control group (P<0.05), Administration of The dexamethasone decreased the TGF-β1and MMP-9nlevels compared with the OVA group (P<0.05). Administration of The Liver-X-Receptors only decreased the TGF-β1levels compared with the OVA group. Conclusion:The Liver-X-Receptors alleviate the AHR and airway remodeling in a murine model of chronic asthma but have no influence in the airway inflammation...