CN112007146A - Il-22在治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途 - Google Patents
Il-22在治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途 Download PDFInfo
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- CN112007146A CN112007146A CN202010914168.9A CN202010914168A CN112007146A CN 112007146 A CN112007146 A CN 112007146A CN 202010914168 A CN202010914168 A CN 202010914168A CN 112007146 A CN112007146 A CN 112007146A
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Abstract
本发明涉及生物医药领域，具体而言，涉及一种IL‑22在治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。通过取肝组织检测IL‑22对小鼠肝组织损伤严重程度的影响。结果显示IL22可以显著减轻小鼠肝脏损伤程度，同时明显减少肝脏损伤指标ALT、AST的水平。因此IL‑22能够有效减轻脓毒症诱发的肝脏损伤。
Description
技术领域
本发明涉及生物医药领域，具体而言，涉及一种IL-22在治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。
背景技术
脓毒症(sepsis)被定义为机体对感染反应失调而导致的危及生命的器官功能障碍。脓毒症多由机体感染引起，病原体包括病毒、细菌、真菌及寄生虫等。合并严重基础疾病的患者(如糖尿病、慢性阻塞性支气管、白血病、再生障碍型贫血等)、严重创伤、烧伤、大手术后已发生脓毒症，恶化进展为脓毒性休克、多器官衰竭甚至死亡，是重症监护室患者死亡主要原因。肝脏在免疫反应中扮演关键角色，可以释放大量的炎症因子，同时，肝脏也是炎性损伤的首要靶器官。脓毒症相关性肝损伤(SALI)是脓毒症常见临床并发症，是多器官功能障碍和脓毒症致死亡的独立危险因素。如何有效降低脓毒症相关肝损伤对改善脓毒症患者预后至关重要。
白介素-22(Interleukin-22,IL-22)是辅助性T细胞Th17、Th22、自然杀伤性细胞(natural killer，NK)细胞产生的IL-10细胞家族成员之一，参与炎症反应。大量证据表明：IL-22可以保护上皮组织应对感，促进其再生；此外，IL-22在维持肠道屏障完整性方面起到重要作用。IL-22结合IL-10受体2(IL-10R2)和IL-22受体1(IL-22R1)复合物，激活下游信号通路，如信号转换器和转录激活因子3(STAT3)、c-jun N-末端激酶(JNK)和有丝分裂原活化蛋白激酶(MAPK)途径。
发明内容
本发明涉及IL-22在制备用于治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。
可选的，所述肝脏损伤伴随肝脏炎症。
可选的，所述肝脏损伤伴随IL-6、IL-1β、TNF-α的表达量显著性增加。
可选的，所述脓毒症由微生物感染导致。
可选的，所述脓毒症由革兰氏阴性菌感染导致。
可选的，所述脓毒症包括早期脓毒症、严重脓毒症和脓毒症休克。
可选的，所述药物包括药学上可接受的载体。
可选的，所述药物为冻干粉剂。
可选的，所述药物为注射剂。
可选的，所述注射剂为静脉注射剂或腹腔注射剂。
本发明的有益效果为：
采用腹腔注射LPS诱导制备小鼠脓毒症模型，实验组使用IL-22重组蛋白进行腹腔注射，检测IL-22对脓毒症模型小鼠血清中各炎症因子的影响。结果显示，使用IL-22治疗后，IL-1β、IL-6及TNF-α显著降低。因此本发明提供了IL-22在制备用于治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，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，还可以根据这些附图获得其他的附图。
图1为本发明一个实施例中脓毒症小鼠血清中IL-6、ALT及AST的表达量检测；
图2为本发明一个实施例中脓毒症小鼠肝组织的HE染色结果；
图3为本发明一个实施例中脓毒症小鼠肝组织炎症因子检测结果。
具体实施方式
现将详细地提供本发明实施方式的参考，其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上，对本领域技术人员而言，显而易见的是，可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如，作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中，来产生更进一步的实施方式。
因此，旨在本发明覆盖落入所附权利要求的范围及其等同范围中的此类修改和变化。本发明的其它对象、特征和方面公开于以下详细描述中或从中是显而易见的。本领域普通技术人员应理解本讨论仅是示例性实施方式的描述，而非意在限制本发明更广阔的方面。
本发明涉及IL-22在制备用于治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。
通过取肝组织检测IL-22对小鼠肝组织损伤严重程度的影响。结果显示IL22可以显著减轻小鼠肝脏损伤程度，同时明显减少肝脏损伤指标ALT、AST的水平。因此IL-22能够有效减轻脓毒症诱发的肝脏损伤。
通过血清检测及HE染色首次证明IL-22可以有效减轻小鼠炎症反应，减轻小鼠肝脏损伤，发挥治疗脓毒症的作用。因此本发明提供了IL22在治疗脓毒症诱发的肝脏损伤中的用途。
在一些实施方式中，所述肝脏损伤伴随肝脏炎症。
在一些实施方式中，所述肝脏损伤伴随IL-6、IL-1β、TNF-α的表达量显著性增加。
在一些实施方式中，所述脓毒症由微生物感染导致。
已知引起脓毒症的感染微生物包括，但不限于：革兰氏阴性细菌如大肠杆菌(E.coli)、克雷白式杆菌属、绿脓杆菌和肠杆菌；及革兰氏阳性菌如表皮葡萄球菌和粪链球菌。
在一些实施方式中，所述脓毒症由革兰氏阴性菌感染导致。
由革兰氏阴性细菌产生的细菌产生的细菌内毒素为细菌膜脂多糖(lipopolysaccharide，LPS)。脂多糖内毒素触发一系列导致脓毒症，并最终可能导致脓毒性休克和死亡链锁现象，具体地说，在应答这些脂多糖的存在中，释放出炎症反应介质包括但不限于肿瘤坏死因子、白细胞介素、血小板激活因子、白细胞三烯、前列腺素、干扰素、血小板、舒缓肽。释放炎症反应介质会引起细胞损伤，这种损伤最后导致细胞破坏，并最终导致器官的死亡。
在一些实施方式中，所述脓毒症包括早期脓毒症、严重脓毒症和脓毒症休克。
在一些实施方式中，所述药物包括药学上可接受的载体。
药学上可接受的载体成分的实例包括结合剂(糖浆、阿拉伯树胶、明胶、山梨醇、黄芪胶(tragacanth)、聚乙烯吡咯烷酮等)、填充剂(乳糖、蔗糖、淀粉、磷酸钙、山梨糖醇、甘氨酸等)、润滑剂(硬脂酸镁、滑石、聚乙二醇等)、崩解剂(淀粉、微晶纤维素(microcrystalline cellulose)等)、湿润剂(十二烷基硫酸钠(sodium lauryl sulphate)等)、悬浮剂(山梨糖醇、糖浆、甲基纤维素、葡萄糖浆(glucose syrup)、明胶、氢化食用脂肪等)、乳化剂(卵磷脂、山梨醇单油酸酯、阿拉伯树胶等)、非水性载体(杏仁油、分馏椰子油或甘油、丙二醇、乙醇等疏水酯等)、防腐剂(对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、山梨酸等)、芳香剂(合成香料、天然香料等)、甜味剂(蔗糖、甜叶菊、木糖醇等)、pH调节剂(碳酸氢钠、碳酸钾等)、粉剂(色素、染料、树脂等)、增稠剂(阿拉伯树胶、甲基纤维素等)、抗氧化剂(维生素C、维生素E等)等等。
只要所述试剂可以被给药，本发明的药物可以制成片剂、丸剂、粉剂、颗粒剂、胶囊剂、液体和溶液、悬浮液、乳液、注射剂和滴剂等。
在一些实施方式中，所述药物为冻干粉剂。
在一些实施方式中，所述药物为注射剂。
在一些实施方式中，所述注射剂为静脉注射剂或腹腔注射剂。
本发明优选的给药方式是静脉注射或腹腔注射；也可以通过任何已知的给药方法施用IL-22，例如，从口服、皮粘膜给药(如表面、舌下、鼻腔内和直肠)，非肠道给药(如，经皮下注射、肌内注射、关节内注射、静脉注射、动脉注射)及吸入法给药等中进行适当地选择。因此，具体的给药方式包括，但不限于例如口服、经皮、粘膜、舌下、肌内、静脉、腹膜内、皮下给药及局部用药。
也可以同抗生素或其他细胞因子等能够治疗脓毒症的药物共同施用IL-22。术语“共同施用”，如本文所用，意指用所有类型的助剂(即，复合)给主体下药：同步地(同时)和继后地[一种药紧随另一种药后(服用)或一种药在另一种药服用片刻后(施用)]。例如可以将IL-22与某些抗生素药剂包括但不限于青霉素类、头孢菌素类、Ciprofloxacin、喹诺酮内酰胺抗生素、红霉素和氨基糖或类抗生素共同施用。
经静脉注射给药的药物，一般是固体的灭菌组合物形式。这些组合物还可以含有添加剂，特别是甘露醇、右旋糖苷、水解明胶、柠檬酸钠、甘氨酸等。在使用时溶解于灭菌注射用水或其它注射用灭菌介质中。
经静脉注射给药的人尿激肽原酶组合物也可以是水溶液形式。组合物还可以含有添加剂，特别是甘露醇、氯化钠、葡萄糖等。
药物制剂优选为单位剂量形式。在这种形式中，制剂被细分为含有合适量的活性组分的单位剂量。单位剂量形式可以是包装的制剂，该包装含有分立的制剂量，诸如小瓶或安瓿中的包装片剂、胶囊和粉剂。而且，单位剂量形式可以是胶囊、片剂、扁囊剂或锭剂本身，或者其可以是合适数量的这些剂量形式中任意一种的包装形式。用于口服给药的片剂或胶囊和用于静脉内给药和持续输注的液体是优选的组合物。
根据本发明的再一方面，还涉及一种治疗、预防脓毒症的方法，包括对受试者给予安全和有效量的如上所述药物的步骤。
短语“安全和有效量的”。如本文所用，意指在合理的医药调节范围内化合物或组合物的量大到足以明显有效地缓解所治疗的症状或病症，但小到足以避免严重的副作用(以合理的有益/危险比率)。本发明的方法所用的药物组合物中的活性成份的安全和有效量随所治疗的特定症状、年龄和所治疗患者的身体状况，疾病的严重性、治疗时间、同期治疗情况、使用的特定活性成份、使用的特定的药物学可接受的赋形剂及包括参与治疗医师的知识和技能在内的这类因素的不同而不同。
本发明中所述的术语“受试者”可以指患者或者其它接受本发明所述试剂或药物以治疗、预防、减轻和/或缓解本申请所述疾病、病症、症状的动物，受试者包括温血动物，诸如哺乳类，像是灵长类，且较佳地是人类。非人类的灵长类也是个体。用语个体包括驯养动物，诸如猫、狗等，家畜(举例来说，牛、马、猪、绵羊、山羊等)以及实验动物(举例来说，小鼠、兔、大鼠、沙鼠、豚鼠等)。
在本发明的一种实施方式中，局部地或全身地或通过两种途径组合地施用药物。
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。对于本领域技术人员来说，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。除非特别说明，以下实施例所用试剂和材料均为市购。
除非另有说明，本发明采用的免疫学、生物化学、化学、分子生物学、微生物学、细胞生物学、基因组学和重组DNA等是本领域的常规技能。参见萨姆布鲁克(Sambrook)、弗里奇(Fritsch)和马尼亚蒂斯(Maniatis)，《分子克隆：实验室手册》(MOLECULAR CLONING:ALABORATORY MANUAL)，第2次编辑(1989)；《当代分子生物学实验手册》(CURRENT PROTOCOLSIN MOLECULAR BIOLOGY)(F.M.奥苏贝尔(F.M.Ausubel)等人编辑，(1987))；《酶学方法》(METHODS IN ENZYMOLOGY)系列(学术出版公司)：《PCR2:实用方法》(PCR 2:A PRACTICALAPPROACH)(M.J.麦克弗森(M.J.MacPherson)、B.D.黑姆斯(B.D.Hames)和G.R.泰勒(G.R.Taylor)编辑(1995))、哈洛(Harlow)和拉内(Lane)编辑(1988)《抗体：实验室手册》(ANTIBODIES,A LABORATORY MANUAL)，以及《动物细胞培养》(ANIMAL CELL CULTURE)(R.I.弗雷谢尼(R.I.Freshney)编辑(1987))。
实施例
一、试验方法：
1、实验动物及材料:
实验小鼠购自上海南方模式实验动物中心，均为清洁级健康雄性C57BL/6J小鼠，共24只，年龄在8～12周，体重20～25g。
白细胞介素-22，50μg溶解于500μlPBS溶液中制得IL-22溶液。
给药剂量：每只小鼠体重给予500ng白细胞介素-22溶液。
2、模型制备：
腹腔注射LPS诱导制备小鼠脓毒症模型：实验组小鼠尾静脉给药IL22，以500ng/只的剂量预处理4天，对照组小鼠同时给予尾静脉相同剂量的PBS预处理4天，后腹部消毒，实验组小鼠腹腔注射LPS(5mg/kg)，对照组小鼠给予相同剂量的PBS腹腔注射。经24小时后收集小鼠血清和肝脏-80℃保存，4％甲醛溶液固定小鼠肝组织待用。
3、小鼠血清检测：
使用检测试剂盒检测小鼠血清ALT和AST浓度，使用联科生物公司小鼠细胞因子/趋化因子检测试剂盒检测小鼠血清IL-6的表达。
4、小鼠肝组织损伤严重程度的检测
将肝组织固定，包埋，切片，并用苏木精和曙红(hematoxylin and eosin，H&E)染色进行组织病理学分析。
根据以下四个肝损伤评分指标评判：1肝小叶充血；2出血；3炎性细胞浸润或聚集；4肝小叶结构的完整性和清晰度。
5、小鼠肝组织炎症因子检测
将肝组织用TRIzol充分裂解提取肝脏RNA，使用TAKARAA的反转录试剂盒将RNA逆转录为DNA,再使用TAKARAA的荧光半定量试剂盒检测肝组织中炎症因子IL-1β、IL-6及TNF-α的表达。
使用“Light cycler 96”软件进行结果分析后进行统计学分析，并使用“graphpad”软件制柱状图。
6、统计学分析
应用SPSS 19.0软件进行统计学分析，计量资料以均数加减标准差表示。同一时间，不同组间比较采用t检验；不同时间、不同组间采用双因素方差分析(Two-way ANOVA)，P<0.05表明差异有统计学意义。
二、实验结果：
1、血清检测：
脓毒症小鼠血清检测结果显示，使用IL-22治疗后，IL-6、ALT及AST显著降低(图1)。
2、HE染色结果：
小鼠肝组织损伤严重程度的检测结果显示IL-22可以显著减轻小鼠肝脏损伤程度(图2)。
3、肝组织炎症因子检测：
IL-6、IL-1β、TNF-α是肝脏损伤的重要炎症指标，结果显示IL-22作用下可显著降低肝脏损伤炎症指标(图3)。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.IL-22在制备用于治疗和/或预防脓毒症诱发的肝脏损伤的药物中的用途。
2.根据权利要求1所述的用途，所述肝脏损伤伴随肝脏炎症。
3.根据权利要求2所述的用途，所述肝脏损伤伴随IL-6、IL-1β、TNF-α的表达量显著性增加。
4.根据权利要求1所述的用途，所述脓毒症由微生物感染导致。
5.根据权利要求4所述的用途，所述脓毒症由革兰氏阴性菌感染导致。
6.根据权利要求1所述的用途，所述脓毒症包括早期脓毒症、严重脓毒症和脓毒症休克。
7.根据权利要求1所述的用途，所述药物包括药学上可接受的载体。
8.根据权利要求1所述的用途，所述药物为冻干粉剂。
9.根据权利要求1所述的用途，所述药物为注射剂。
10.根据权利要求9所述的用途，所述注射剂为静脉注射剂或腹腔注射剂。
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| US20140314711A1 (en) * | 2013-03-15 | 2014-10-23 | Genentech, Inc. | IL-22 POLYPEPTIDES AND IL-22 Fc FUSION PROTEINS AND METHODS OF USE |
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| CN102348463A (zh) * | 2009-01-12 | 2012-02-08 | 健能隆医药技术（上海）有限公司 | 白介素-22在预防和/或治疗多器官功能障碍综合症(mods)中的用途 |
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