背景:小青龙汤(XQLD),首先记录在《尚汉论》中,是用于治疗过敏性鼻炎(AR)的传统中药。XQLD通过抑制炎症反应的发生来缓解AR的临床症状,但具体的监管机制尚不清楚。
目的:NLRP3介导的焦亡与AR发病密切相关。因此,本研究旨在探讨NLRP3介导的焦亡通路在XQLD相关AR药理机制中的潜在作用。
方法:采用卵清蛋白(OVA)和氢氧化铝致敏方法建立BALB/C小鼠AR模型。不同剂量的XQLD灌胃后,观察鼻腔过敏症状。ELISA法检测血清中OVA-sIgE和Th2炎症因子(IL-4、IL-5、IL-13)的表达。观察鼻黏膜组织病理学形态及炎症因子的表达情况。进行分子对接以分析XQLD的代表性化合物与NLRP3的结合。通过免疫荧光和蛋白质印迹检测NLRP3炎性体的激活。
结果:XQLD显著改善了小鼠的鼻过敏症状,降低杯状细胞增殖的程度,肥大细胞浸润,鼻粘膜胶原纤维增生。同时,它可以下调血清和鼻黏膜中Th2炎症因子(IL-4,IL-5和IL-13)的表达。XQLD显著降低GSDMD和TUNEL双阳性细胞的数量以及IL-1β和IL-18的表达。分子对接证实XQLD的7个代表性化合物与NLRP3具有良好的结合性质,并且能够抑制NLRP3炎性体的活化。
结论:XQLD的代表化合物可能抑制NLRP3炎性体介导的鼻黏膜细胞焦凋亡,有助于AR的恢复。这为XQLD治疗AR提供了新的现代药理学证据。
BACKGROUND: Xiaoqinglong decoction (XQLD), first recorded in Shang Han Lun, is a traditional Chinese medicine prescribed for the treatment of allergic rhinitis (AR). XQLD alleviates the clinical symptoms of AR by inhibiting the occurrence of an inflammatory response, but the specific regulatory mechanism remains unclear.
OBJECTIVE: NLRP3-mediated pyroptosis is closely related to AR pathogenesis. Hence, this study aimed to explore the potential role of NLRP3-mediated pyroptosis pathway in the AR-associated pharmacological mechanism of XQLD.
METHODS: BALB/C mice models of AR was established by using ovalbumin (OVA) and aluminum hydroxide sensitization. After intragastric administration of different dosages of XQLD, nasal allergic symptoms were observed. The expression of OVA-sIgE and Th2 inflammatory factors (IL-4, IL-5, and IL-13) in serum was detected by ELISA. The histopathological morphology and expression of inflammatory factors in nasal mucosa along with pyroptosis were investigated. Molecular docking was performed to analyze the binding of representative compounds of XQLD with NLRP3. Activation of the NLRP3 inflammasome was detected by immunofluorescence and western blotting.
RESULTS: XQLD significantly improved the nasal allergic symptoms of mice, reduced the degree of goblet cell proliferation, mast cell infiltration, and collagen fiber hyperplasia in nasal mucosa. Meanwhile, it could downregulate the expression of Th2 inflammatory factors (IL-4, IL-5, and IL-13) in serum and nasal mucosa. XQLD significantly reduced the number of GSDMD and TUNEL double-positive cells and IL-1β and IL-18 expression. Molecular docking confirmed that seven representative compounds of XQLD had good binding properties with NLRP3 and were able to inhibit the activation of the NLRP3 inflammasome.
CONCLUSIONS: The representative compounds of XQLD might inhibit pyroptosis in nasal mucosa mediated by the NLRP3 inflammasome to helping the recovery of AR, which provides a new modern pharmacological proof for XQLD to treat AR.