Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergeninduced airway inflammation and eosinophilia in a murine model of asthma
Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergeninduced airway inflammation and eosinophilia in a murine model of asthma
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DOI：
10.1016/j.jaci.2006.02.047
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发表时间：
2006-07-01
影响因子：
14.2
通讯作者：
Wang, Jiu-Yao
中科院分区：
文献类型：
--
作者：
Chen, Chih-Lung;Wang, Shulhn-Der;Wang, Jiu-Yao
背景：肥大细胞类胰蛋白酶和某些过敏原等丝氨酸蛋白酶在哮喘过敏性炎症的发病机制中发挥着重要作用。目的：我们旨在研究丝氨酸蛋白酶抑制剂甲磺酸萘莫司他（FUT）、甲磺酸加贝酯（FOY）和乌司他丁（UTI）对过敏性哮喘小鼠模型气道炎症的影响。方法：BALB/c小鼠对螨螨过敏。 pteronyssinus (Der p) 并用 Der p (0.5 mg/mL) 进行气管内攻击。在致敏阶段（方案1）或过敏原攻击后24小时（方案2）将治疗剂量的FUT（0.0625 mg/kg）、FOY（20 mg/kg）和UTI（10,000 U/kg）腹腔注射到3只相应的致敏小鼠中。结果：FUT治疗和FOY治疗的致敏小鼠的肥大均减少与未治疗的小鼠相比，细胞活化、气道高反应性、嗜酸性粒细胞浸润减弱以及 Der p 诱导的 IL-4 和 TNF-α 减少，但支气管肺泡灌洗液中 IL-12 细胞因子的产生增加。此外，FUT 治疗下调了 Der p 刺激的肺泡巨噬细胞中 IL-1β、TNF-α、IL-6、eotaxin、诱导型 NO 合酶、CD86 和核因子-κ B 激活的表达，但增强了 IL-12 和 IL-10 的表达。 UTI处理的小鼠与未处理的致敏小鼠相比，上述指标无明显变化。 结论：甲磺酸萘莫司他和FOY对过敏原诱导的气道炎症发挥治疗作用，不仅是其对肥大细胞激活早期的抑制作用，而且是过敏炎症后期免疫调节功能的结果。 FUT和FOY的这些特性可能是哮喘的潜在治疗方法。临床意义：丝氨酸蛋白酶抑制剂FUT和FOY的临床使用也可能对治疗哮喘气道炎症有影响。
Background: Serine proteases such as mast cell tryptase and certain allergens are important in the pathogenesis of allergic inflammation of asthma.Objective: We sought to investigate the effects of serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on airway inflammation in a mouse model of allergic asthma.Methods: BALB/c mice were sensitized to Dermatophagoides pteronyssinus (Der p) and intratracheally challenged with Der p (0.5 mg/mL). Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), and UTI (10,000 U/kg) were intra-peritoneally injected into 3 corresponding sensitized mice during the sensitization phase (protocol 1) or 24 hours after allergen challenge (protocol 2).Results: Both FUT-treated and FOY-treated sensitized mice had reduced mast cells activation, airway hyperresponsiveness, attenuated eosinophils infiltrations, and decreased Der p-induced IL-4 and TNF-alpha, but increased IL-12 cytokine production in bronchoalveolar lavage fluid compared with nontreated mice. Furthermore, FUT treatment downregulated the expression of IL-1 beta, TNF-alpha, IL-6, eotaxin, inducible NO synthase, CD86, and nuclear factor-kappa B activation, but enhanced the expression of IL-12 and IL-10 in Der p-stimulated alveolar macrophages. UTI-treated mice have no significant change of the aforementioned measurements compared with nontreated sensitized mice.Conclusion: Nafamostat mesilate and FOY exerting the therapeutic effect in allergen-induced airway inflammation was a result not only of their inhibitory action in the early phase of mast cells activation but also of immunoregulatory function in the late phase of allergic inflammation. Such properties of FUT and FOY might be a potential therapeutic approach for asthma.Clinical implications: The clinical used of serine protease inhibitors FUT and FOY may also have implications for treating airway inflammation of asthma.