CN115137832B - 一种jak抑制剂的用途及其抗毛霉感染实验方法 - Google Patents
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Abstract
本发明提供了一种JAK抑制剂的用途及其抗毛霉感染实验方法，首次提出将JAK抑制剂应用于毛霉真菌的生长环境中，为抗毛霉感染的研究提供了新的方向；并通过小鼠实验可以检验JAK抑制剂针对抗毛霉感染的实际辅助作用，对于抗毛霉感染的研究具有非常积极的意义。
Description
技术领域
本发明涉及一种JAK抑制剂的用途及其抗毛霉感染实验方法，属于医学真菌学技术领域。
背景技术
毛霉病(mucormycosis)是由人体吸入、摄入或外伤后接触毛霉目真菌(Mucorales)所引发的机会性感染。澳大利亚和新西兰真菌病兴趣小组(Australia andNew Zealand Mycoses Interest Group，ANZMIG)开展一项多中心回顾性观察研究，对2004年至2012年间成人非曲霉霉菌感染进行分析发现，毛霉病已经成为继曲霉菌感染外第二多见的致病霉菌。
JAK抑制剂在感染中已有相关应用，近期研究表明JAK抑制剂可以让新冠肺炎感染者受益。药效学和临床研究结果已显示JAK抑制剂能够显著抑制多种免疫炎症疾病的发生和发展，而新型冠状病毒感染能够引起部分患者出现全身过度免疫炎症反应(细胞因子风暴)或肺组织炎症，进而导致重症肺炎，甚至危及生命，JAK抑制剂可以通过抑制这些过度免疫炎症反应，达到治疗重症肺炎的目的。在毛霉病中，同样可以诱发严重免疫炎症反应或组织损伤。诸多不规则毛霉临床病例提示，尽管积极进行抗真菌治疗，但仍然造成不可逆转的组织破坏。抗真菌联合小剂量激素抗炎的方法虽可用于治疗炎症重的脓癣等，但在毛霉病等深部真菌感染中仍被视为禁忌，故更宜选用新型抗炎药。JAK1抑制剂靶向作用于宿主而不影响真菌的生长或形态，不易诱导真菌耐药，更具潜在优势。
鉴此，发现JAK抑制剂的新用途，以及在毛霉感染实验中的应用，对于抗毛霉感染的研究具有非常积极的意义。
发明内容
针对上述存在的技术问题，本发明的目的是：提出了一种JAK抑制剂的用途及其抗毛霉感染实验方法。
本发明的技术解决方案是这样实现的：一种JAK抑制剂的用途，将JAK抑制剂应用于毛霉真菌的生长环境中。
优选的，所述JAK抑制剂为Filgotinib(GLPG0634，Selleck)。
优选的，将JAK抑制剂与抗真菌药物联合使用。
优选的，所述抗真菌药物包含两性霉素B及其脂质体、泊沙康唑、艾沙康唑、伊曲康唑、伏立康唑。
优选的，所述JAK抑制剂和抗真菌药物为口服制剂、注射制剂或外用制剂。
一种JAK抑制剂的抗毛霉感染实验方法，包含以下步骤：
①制备真菌样本，准备菌悬液；
②以多组ICR小鼠为实验动物，在尾部区域后背备皮后，皮内注射菌悬液形成局部的皮丘；
③将一组皮内注射处理后的小鼠作为阴性对照组；
④将一组皮内注射处理后的小鼠作为JAK抑制剂处理组；
⑤将一组皮内注射处理后的小鼠作为抗真菌药物处理组；
⑥将一组皮内注射处理后的小鼠作为JAK抑制剂和抗真菌药物联合用药组；
⑦对比各组小鼠的皮损组织病理情况。
优选的，所述JAK抑制剂采用灌胃的方式。
优选的，所述抗真菌药物组采用注射的方式。
优选的，所述JAK抑制剂为Filgotinib(10mg/kg/d)。
优选的，所述抗真菌药物为两性霉素(1mg/kg/d)。
由于上述技术方案的运用，本发明与现有技术相比具有下列优点：
本方案提供了一种JAK抑制剂的用途及其抗毛霉感染实验方法，首次提出将JAK抑制剂应用于毛霉真菌的生长环境中，为抗毛霉感染的研究提供了新的方向；并通过小鼠实验可以检验JAK抑制剂针对抗毛霉感染的实际辅助作用，对于抗毛霉感染的研究具有非常积极的意义。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对本发明实施例描述中所需要使用的附图作简单的介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据本发明实施例的内容和这些附图获得其他的附图。
附图1为小鼠感染模型的图片；
附图2为小鼠感染模型的脓肿大小结果图；
附图3为HE染色图。
具体实施方式
为使本发明解决的技术问题、采用的技术方案和达到的技术效果更加清楚，下面将结合附图对本发明实施例的技术方案作进一步的详细描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明提出了一种JAK抑制剂的用途，是JAK抑制剂在抗毛霉感染中的应用，具体是将JAK抑制剂应用于毛霉真菌的生长环境中，可以为抗毛霉感染的实验和实施措施提供新的思路。
本发明依据早期的研究报道和一系列的创新性实验，选用Filgotinib，Filgotinib是一种选择性JAK1抑制剂，本研究选用的Filgotinib(GLPG0634，Selleck)对JAK1，JAK2，JAK3和TYK2的IC50值分别为10nM，28nM，810nM和116nM。
申请人通过研究发现，口服Filgotinib(10mg/kg/d)可以改善小鼠毛霉病模型皮损的炎症反应，即以中性粒细胞和巨噬细胞为主要炎细胞聚集所造成的炎性反应。此外，口服Filgotinib(10mg/kg/d)联合腹腔注射两性霉素(1mg/kg/d)后能更加明显的改善小鼠毛霉病模型皮损的大体皮损情况。
因此，本申请要求保护Filgotinib(10mg/kg/d)在抗毛霉感染中的研究方案及应用，以及Filgotinib(10mg/kg/d)联合两性霉素(1mg/kg/d)抗毛霉感染的研究方案及应用。
进一步地，已获批上市及正处于临床试验阶段的JAK1抑制剂还有Tofacitinib-citrate，Upadacitinib和Itacitinib等，都具有靶向作用于JAK1抑制免疫炎症的作用和协同对抗毛霉感染的潜能，也应当在本方案的保护范围中。
更进一步地，除上述JAK1抑制剂的单作用外，上述JAK1抑制剂联合抗真菌药物在抗毛霉感染中的研究方案及应用也应当在本方案的保护范围中。
优选地，抗真菌药物主要包括两性霉素B及其脂质体、泊沙康唑、艾沙康唑、伊曲康唑、伏立康唑等，但不局限于上述抗真菌药物。
再进一步地，所述JAK1抑制剂和抗真菌药物为口服制剂、注射制剂或外用制剂。
本方案还提供了一种JAK抑制剂的抗毛霉感染实验方法，包含以下步骤：
①制备真菌样本；
取麦芽提取物琼脂培养基上不规则毛霉孢子，PBS清洗2次后重悬于YPD培养基中，计数后孢子混悬液浓度为1×107/ml，以200rpm的速度在30℃条件下摇菌12小时，显微镜下观察看到超过50％的萌芽孢子，PBS清洗2次后重悬于PBS中，计数后孢子混悬液浓度为1×107/ml，备用。
②准备ICR小鼠感染模型；
以多组6-8周龄的雄性ICR小鼠为实验动物，近尾部区域后背备皮后，皮内注射0.1ml上述备用菌悬液形成局部的皮丘，将处理后的小鼠饲养7天。
③将一组皮内注射处理后的小鼠灌胃PBS溶液，连续灌胃3天，作为阴性对照组；
④将一组皮内注射处理后的小鼠灌胃Filgotinib 10mg/kg/d，连续灌胃3天，作为JAK抑制剂处理组；
⑤将一组皮内注射处理后的小鼠腹腔注射两性霉素(1mg/kg/d)，连续给药3天，作为抗真菌药物处理组；
⑥将一组皮内注射处理后的小鼠灌胃Filgotinib 10mg/kg/d，连续灌胃3天，同时腹腔注射两性霉素(1mg/kg/d)，连续给药3天，作为JAK抑制剂和抗真菌药物联合用药组；
⑦将饲养7天后的各组小鼠局部皮损取材后，用4％多聚甲醛浸泡固定后行HE染色和炎症相关因子的组化染色，并对比各组小鼠的皮损组织病理情况。
参考图1，其中：A.阴性对照组；B.JAK抑制剂处理组(Filgotinib(10mg/kg/d)灌胃处理组)；C.抗真菌药物处理组(两性霉素(1mg/kg/d)腹腔注射组)；D.联合用药组。
参考图2，其中：control：阴性对照组；AmB：抗真菌药物处理组；Filgotinib：JAK抑制剂处理组；AmB+Filgotinib：联合用药组。结果显示在小鼠感染模型大体上，单用AmB和联合用药组脓肿的大小都较对照组有明显的减小，但两组间无统计学差异。
参考图3，HE染色(×100)，其中：A.阴性对照组；B.JAK抑制剂处理组；C.抗真菌药物处理组；D.联合用药组。
结论：
不规则毛霉小鼠感染模型造模后，给予不同的处理方案，最终结果显示，不同处理下的小鼠都出现了不同程度的皮下脓肿，大小不同(图1)。通过对每个处理组小鼠皮下脓肿大小的测量，我们发现结单用AmB和联合用药组脓肿的大小都较对照组有明显的减小，说明两组用药对于减小感染局部的脓肿都有较好的作用，但两组间进行比较发现无统计学差异(图2)。
进一步地，皮损组织病理学检查结果发现每组的实验小鼠皮损内都可见粗大的菌丝和大小不一的孢子，但联合用药组的镜下包块较其他组明显更小，镜下的炎症反应更轻。
综合以上分析，我们认为在小鼠皮肤毛霉感染的实验中，口服Filgotinib(10mg/kg/d)联合腹腔注射两性霉素(1mg/kg/d)有明显的抗真菌及抗炎疗效，有进一步为抗毛霉感染临床实验提供新方案的潜在可能。
本发明提出了上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并加以实施，并不能以此限制本发明的保护范围，凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围内。
Claims (4)
1.一种JAK抑制剂在制备抗毛霉感染的药物中的用途，其特征在于：将JAK抑制剂应用于毛霉真菌的生长环境中；所述JAK抑制剂为Filgotinib或GLPG0634。
2.根据权利要求1所述的JAK抑制剂在制备抗毛霉感染的药物中的用途，其特征在于：将JAK抑制剂与抗真菌药物联合使用。
3.根据权利要求2所述的JAK抑制剂在制备抗毛霉感染的药物中的用途，其特征在于：所述抗真菌药物包含两性霉素B、泊沙康唑、艾沙康唑、伊曲康唑、伏立康唑。
4.根据权利要求2所述的JAK抑制剂在制备抗毛霉感染的药物中的用途，其特征在于：所述JAK抑制剂和抗真菌药物为口服制剂、注射制剂或外用制剂。
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| WO2020052575A1 (zh) * | 2018-09-12 | 2020-03-19 | 江苏恒瑞医药股份有限公司 | Jak激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤疾病的药物中的用途 |
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| WO2013149194A1 (en) * | 2012-03-29 | 2013-10-03 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
| WO2020052575A1 (zh) * | 2018-09-12 | 2020-03-19 | 江苏恒瑞医药股份有限公司 | Jak激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤疾病的药物中的用途 |
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