P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps
P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps
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DOI：
10.4193/rhin20.551
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发表时间：
2021-01-01
期刊：
影响因子：
7.2
通讯作者：
Bleier, Benjamin S.
中科院分区：
文献类型：
--
作者：
Taha, Maie S.;Nocera, Angela;Bleier, Benjamin S.
工作背景：P-糖蛋白（P-gp）是一种膜外排泵，在慢性鼻窦炎伴鼻息肉（CRSwNP）中过度表达，并促进2型炎症。糖皮质激素（GC）是P-gp的底物，表明过表达可能另外导致CRSwNP中的GC抗性。本研究旨在确定是否P-gp抑制使用维拉帕米增强莫米松保留和疗效在鼻息肉explants.Methodology：IRB批准的研究中，器官型息肉外植体暴露于莫米松（4.15微克/毫升）和维拉帕米（125微克/毫升）作为单一和联合治疗。使用HPLC测定维拉帕米对莫米松随时间的组织保留的影响。维拉帕米对莫米松抗炎功能的影响使用分泌的IL-5的ELISA测定。组进行比较，使用Kruskal-Wallis test.Results：P-gp表达强烈，显着负相关与莫米松保留1小时后曝光，与近6倍的组织保留之间的最低和最高的P-gp表达息肉外植体减少。P-gp抑制剂逆转了这种作用，并显著改善了莫米松在1小时时的保留相对于单独莫米松。莫米松和维拉帕米的组合显着降低IL-5分泌相对于车辆控制和优于任何单独的treatment.Conclusions：我们的研究证实，P-gp有助于莫米松耐药。这种P-gp介导的耐药性通过加入P-gp抑制剂维拉帕米成功逆转。维拉帕米作为联合治疗进一步显著增强了莫米松的抗炎作用。
Background: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants.Methodology: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 mu g/mL) and verapamil (125 mu g/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was determined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test.Results: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a nearly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mometasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone.Conclusions: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.