CN115137749A - 过氧化氢在治疗急性肺损伤中的应用 - Google Patents
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Abstract
本发明公开了一种过氧化氢(H2O2)在治疗急性肺损伤中的应用，H2O2用于治疗急性肺损伤，H2O2以治疗有效量使用以实现急性肺损伤的治疗。本发明的实验结果表明，低浓度H2O2能显著降低急性肺损伤小鼠支气管肺泡灌洗液中的炎性因子水平，增强小鼠肺功能，减轻肺组织的病理损伤程度；表明低浓度H2O2对小鼠急性肺损伤具有明显的治疗作用。可用于制备作为任何刺激因素引发的急性肺损伤的药物。
Description
技术领域
本发明属于医药技术领域，具体涉及一种过氧化氢在治疗急性肺损伤中的应用。
背景技术
急性肺损伤(acute lung injury,ALI)是一种由于外部或者是肺内等因素引起的一种肺部炎症反应，导致组成肺泡的上皮细胞及毛细血管内皮细胞的弥漫性损伤，最终导致患者出现呼吸衰竭。引发急性肺损伤的原因较多，肺部炎症、吸入有毒物质、弥漫性肺部感染、误吸胃部反流液等属于直接原因。而急性胰腺炎、大量输血、脓毒血症、严重创伤性休克、药物使用过量、体外循环等则属于间接因素。目前，机体因此感染如细菌、病毒感染引发的免疫炎症反应失衡所致的脓毒症性ALI最为常见，其发生率可达50％以上，病死率高达50-70％，由ALI进展为急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)死亡率可达70％。更为重要的是，ALI是导致其它重要脏器发生多器官功能障碍综合征(multiple organ dysfunctionsyndrome，MODS) 的重要诱因。ALI/ARDS临床主要表现为急性进行性加重的呼吸困难和顽固性低氧血症，极易并发呼吸衰竭危及患者生命；而预后肺功能也很难恢复到正常状态，且易发展为肺纤维化。大量研究表明，肺组织内过度炎症反应和高氧化应激状态是其主要病理生理特点，由此引起的肺泡上皮细胞的损害是 ALI/ARDS的主要病理学基础，其损伤程度直接影响肺功能，决定患者的预后。 ALI/ARDS的临床治疗手段，主要有药物治疗、机械式通气两种手段，使用保护性的呼吸机治疗策略，虽然可以为治疗急性肺损伤患者起到一定的帮助，但是未能有效降低患者死亡率。而药物治疗作为近几年对急性肺损伤患者采用的一种综合性的临床治疗手段，已经取得了一定的研究进展，但仍然没有特效的 ALI治疗药物。
急性肺损伤的病理基础是弥漫性肺泡上皮及血管内皮细胞的损害，由此造成肺泡结构及相应的气血屏障的破坏，针对ALI发病这一关键环节，有效促进肺泡修复与再生，恢复正常的气血屏障结构是治疗ALI的关键。由此，有研究证实，应用肝细胞生长因子、血管内皮细胞生长因子(VEGF)、αFGF、表皮生长因子(EGF)类蛋白(包括双调蛋白(Areg)、EGF、转化生长因子α (TGF-α)、细胞调节素(BTC)、肝素结合性表皮生长因子(HB-EGF)、上皮调节蛋白(Ereg)以及神经调节蛋白(NRG)、FGF-10以及新近发现的髓源性生长因子(myeloid-derived growth factor，MYDGF)等，均能有效减轻肺水肿及减少蛋白等大分子物质进入肺泡腔，显著改善肺功能，对ALI具有保护作用。这些因子通过与其相应的受体结合，促进肺细胞的生存、增殖与分化。通过促进肺泡Ⅱ型上皮细胞(AEC2)增殖、趋化、迁移以及向AEC1的分化和肺内皮细胞的增殖，促进损伤肺泡结构的再生与修复，修复和维护气血屏障结构的完整性；研究还发现，生长因子不仅能促进AEC2的增殖和分化，还能增加其表面活性蛋白(SPC-A、C)的合成(急性肺损伤时，肺表面活性蛋白的表达明显降低)，从而改善肺泡表面张力，维持肺泡的功能稳态，对气血屏障的稳定有一定作用。此外，间充质干细胞(MSC)对ALI/ARDS治疗的有效性也被大量的动物实验和临床实践证实，其治疗作用机制之一就是通过旁分泌生长因子促进肺上皮细胞和血管内皮细胞的修复。最终这些生长因子主要通过活化PI3K和Akt信号通路抑制肺细胞凋亡，通过MAPK1/3、STAT3和细胞周期蛋白D1的信号通路增强肺上皮和内皮细胞增殖。生长因子对各种刺激因子造成的ALI及气道损伤均有保护作用，其临床应用效果也得以证实。生长因子作为一种蛋白，更适合局部给药，因此，生长因子在ALI的预防和治疗中具有潜在临床价值，对于ALI治疗提供了新策略。
然而，生长因子使用具有高生产成本的缺点。H2O2是具有生长因子样作用的活性分子。H2O2是细胞内活性氧(ROS)最稳定、氧化活性最弱的形式，它参与调控细胞内多种生理过程，如缺氧信号转导、细胞增殖与分化及介导免疫反应。在正常生理情况下，细胞胞浆、线粒体内、核内都有一个稳态的H2O2水平以维持细胞的生理活动，线粒体基质中的浓度为5-20nM，胞浆内大约是 1-100nM。在细胞内生理水平的H2O2维持主要是来源于细胞膜NADPH氧化酶(NOXs)和线粒体电子传递链(ETC)的复合物I和III，细胞内大约40％的H2O2来自NOX，大约45％来自ETC，其余的来自其他酶来源。这种生理性、低水平的H2O2维持及其相关的生理氧化还原信号的状态被称为“氧化正应激”(oxidative eustress)，完全区别于因H2O2浓度过高引起的氧化应激(oxidative stress)，后者可造成细胞不可逆损害。因此，H2O2被认为是细胞非常重要的信号分子，作为第二信使参与细胞增殖、存活、应激等信号通路的调控。在控制细胞这些重要的生理过程中发挥着关键作用。研究证实生长因子发挥作用是通过活化细胞膜上NADPH氧化酶上调细胞内的H2O2水平，以抑制负性调控细胞生成关键信号通路PI3K/Akt的磷酸酶活性实现，由此提示低浓度H2O2具有生长因子作用。研究发现：低于生理阈值的线粒体或细胞质H2O2水平能导致由H2O2调控的特定信号级联下调或丢失，最终引起细胞功能异常。ALI/ARDS 早期肺组织存在强烈的氧化应激，极易引发细胞蛋白、基因及脂质膜等生物大分子物质发生氧化损伤，导致其功能异常。文献证实，ALI时肺上皮NOX氧化酶功能存在异常，可见，细胞内H2O2的主要来源NOX和线粒体ETC均发生损害(因氧化损伤)，最终可能导致ALI后期肺上皮细胞胞浆内H2O2显著低于生理阈值。如果线粒体内H2O2减少至生理水平以下/极低水平，即发生“还原应激”，后者同样会损害线粒体功能导致细胞正常的生理活动抑制、甚至凋亡坏死。这可能是为什么ARDS后期抗氧化治疗效果不佳的主要原因，因此，通过外源性给予低浓度H2O2治疗以恢复细胞内正常的H2O2水平，以促进肺细胞及线粒体功能的恢复，减轻肺病理损伤程度和恢复肺功能。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的主要目的在于提供一种用于治疗急性肺损伤的药物。
本发明的目的是通过以下技术方案实现的：
过氧化氢在治疗急性肺损伤中的应用，过氧化氢用于治疗急性肺损伤，所述过氧化氢以治疗有效量使用以实现急性肺损伤的治疗。
优选地，其中所述急性肺损伤包括但不限于LPS诱导的肺损伤。
优选地，其中所述过氧化氢的浓度为300-500μM。
优选地，其中所述过氧化氢的浓度为400μM。
优选地，其中所述过氧化氢为液体药物。
优选地，其中所述过氧化氢经雾化的给药途径为雾化吸入。
与现有技术相比，本发明至少具有以下优点：
本发明所提供的过氧化氢在治疗急性肺损伤中的应用，本发明实验结果表明：低浓度H2O2能显著降低急性肺损伤小鼠支气管肺泡灌洗液中的炎性因子水平，增强小鼠肺功能，减轻肺组织的病理损伤程度。即表明低浓度H2O2对小鼠急性肺损伤具有明显的治疗作用。可用于制备作为任何刺激因素引发的急性肺损伤的药物。
附图说明
为了更清楚地说明本发明具体实施方式，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。
图1为本发明实施例1中三组小鼠的肺功能结果柱状图；
图2为本发明实施例2中三组小鼠支气管肺泡灌洗液中TNF-α含量柱状图；
图3为本发明实施例2中三组小鼠支气管肺泡灌洗液中IL-6含量柱状图；
图4为本发明实施例2中三组小鼠支气管肺泡灌洗液中IL-1β含量柱状图；
图5为本发明实施例3中对照组小鼠肺组织的HE染色结果；
图6为本发明实施例3中ALI组小鼠肺组织的HE染色结果；
图7为本发明实施例3中治疗组小鼠肺组织的HE染色结果；
图8为本发明实施例3中治疗组小鼠肺组织的SPC和T1α免疫荧光双染结果。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例和附图，进一步阐述本发明，但下述实施例仅仅为本发明的优选实施例，并非全部。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径获得。
下述实施例中所使用的过氧化氢溶液通过如下方法配置：
H2O2为液体状制剂，原始浓度为30％，摩尔浓度为9.908mol/L，使用时按照需要的浓度用生理盐水稀释到终浓度为400μM。
实验所用到的小鼠模型为清洁级6周龄雄性C57BL/6J种小鼠，体重 (20±2)g，购自中国人民解放军陆军特色医学中心实验动物中心。
小鼠急性肺损伤模型建立：将小鼠分为3组，分别为：对照组，ALI组，治疗组。ALI组通过LPS雾化吸入建立肺伤情稳定的小鼠ALI模型(使用空气压缩雾化仪，流速0.2ml/min，致伤舱容器体积850cm3，LPS雾化浓度2mg/ml，持续雾化20min)，经前期多次重复实验表明，雾化致伤12h后肺组织开始出现明显的病理损伤，左右肺组织伤情一致，以伤后24h、72h伤情最重，7天左右恢复正常。
实施例1：H2O2在治疗急性肺损伤小鼠的机体整体的肺功能的影响
对经过LPS雾化后12h和24h后的小鼠，分别用浓度为400uM的过氧化氢溶液雾化治疗，在雾化30h后，无创检测上述三组小鼠(对照组，ALI组，治疗组)的肺功能指标(FinePointe WBP全身体积描积系统(BUXCU Research Systems，Incorporated，Wilmington，NC；Data Sciences International，INC USA)，结果如图1和表1所示：
表1 H2O2治疗对ALI各项肺功能指标的影响
注：
一般指标；@容积指标；&气道阻塞指标；#传导性指标；
通气指标；*与对照组比较，P＜0.05，※与ALI组比较，P＜0.05。
通过表1所示的结果可知，经LPS诱导的ALI组小鼠肺功能明显受损，其肺功能的一般指标、容积指标、气道阻塞指标、传导性指标、通气指标与对照组小鼠相比均有显著性差异(p＜0.05)，而经过H2O2雾化治疗后能有效改善ALI小鼠的肺功能(与ALI组比较，p＜0.05)。
实施例2：H2O2在治疗急性肺损伤小鼠的抗炎水平的影响
对三组小鼠支气管肺泡灌洗：三组小鼠经LPS雾化72h后，进行支气管肺泡灌洗。具体方法为：经气管插管用1ml生理盐水灌洗3次，将回收的肺泡灌洗液3000rpm/min，4℃离心10min，取上清液用ELISA检测试剂盒检测 TNF-α(肿瘤坏死因子)、IL-6(白细胞介素6)、IL-1β(白细胞介素1β)因子水平。
结果如图2-图4所示，经LPS诱导的急性肺损伤组(ALI组)促炎因子 TNF-α、IL-6、IL-1β与对照组相比均显著升高(p＜0.05)，而经过H2O2治疗后，促炎因子TNF-α、IL-6、IL-1β均显著下降，提示H2O2治疗能有效降低肺组织的炎症水平(与ALI组比较，p＜0.05)。
实施例3：H2O2在治疗急性肺损伤小鼠的病理组织的影响
肺组织病理学检查：三组小鼠经LPS雾化72h后，取小鼠左肺组织，用冰生理盐水洗去肺表面血液，立即置于10％福尔马林液中固定，常规石蜡包埋。切片后进行HE染色。
结果表明，如图5-图7所示，通过对三组小鼠进行HE染色(×100)观察发现：ALI组肺水肿明显，肺充血明显，肺泡隔增厚，肺间质和肺泡腔可见明显炎性细胞浸润，部分肺泡结构消失、实变，肺泡腔面积(白色)减少；而治疗组肺的病理损伤明显减轻，尤其是肺水肿明显减轻、炎性细胞浸润减少、肺泡腔面积显著增加，提示H2O2治疗能有效减轻LPS诱导的肺组织损伤。
应用石蜡切片对ALI组和治疗组肺组织的SPC(肺II型细胞)和T1a(肺I 型细胞)进行免疫荧光染色，对免疫荧光结果采用ImageJ软件计算平均荧光强度。结果如图8所示，ALI组肺I型细胞(T1α，红色荧光)减少，II型细胞(SPC，绿色荧光)显著减少，DAPI(蓝色荧光，染细胞核)阳性细胞数明显增多，提示炎性细胞增多；与ALI组比较，治疗组肺II型细胞和I型细胞数量增多，红色和绿色平均荧光强度显著增强，相反，DAPI阳性细胞数量明显少，蓝色平均荧光强度显著减弱，提示H2O2治疗能减少炎性细胞浸润，抑制肺组织炎症反应，同时，能促进肺I型和II型细胞修复，增加其数量。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (6)
1.过氧化氢在治疗急性肺损伤中的应用，其特征在于，过氧化氢用于治疗急性肺损伤，所述过氧化氢以治疗有效量使用以实现急性肺损伤的治疗。
2.根据权利要求1所述的应用，其特征在于，所述急性肺损伤包括但不限于LPS诱导的肺损伤。
3.根据权利要求1所述的应用，其特征在于，所述过氧化氢的浓度为300-500μM。
4.根据权利要求3所述的应用，其特征在于，所述过氧化氢的浓度为400μM。
5.根据权利要求1所述的应用，其特征在于，所述过氧化氢为液体药物。
6.根据权利要求5所述的应用，其特征在于，所述过氧化氢经雾化的给药途径为雾化吸入。
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| RU2807851C1 (ru) * | 2023-04-10 | 2023-11-21 | Александр Ливиевич Ураков | Теплый щелочной раствор перекиси водорода для внутрилегочной инъекции |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095831A (zh) * | 2013-04-02 | 2014-10-15 | 中国药科大学 | 和厚朴酚在制备治疗急性肺损伤药物中的应用 |
| US20200323790A1 (en) * | 2019-04-12 | 2020-10-15 | Chung Shan Medical University | Method for treatment of acute lung injury by use of kirenol |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095831A (zh) * | 2013-04-02 | 2014-10-15 | 中国药科大学 | 和厚朴酚在制备治疗急性肺损伤药物中的应用 |
| US20200323790A1 (en) * | 2019-04-12 | 2020-10-15 | Chung Shan Medical University | Method for treatment of acute lung injury by use of kirenol |
Non-Patent Citations (1)
| Title |
|---|
| 张建初;白明;吴妍雯;张蕾;包滨;: "吸入一氧化氮对急性肺损伤大鼠肺组织炎症的影响", 中国呼吸与危重监护杂志, vol. 6, no. 02, pages 150 - 153 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2807851C1 (ru) * | 2023-04-10 | 2023-11-21 | Александр Ливиевич Ураков | Теплый щелочной раствор перекиси водорода для внутрилегочной инъекции |
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