CN114470163A - 重组人髓源性生长因子在治疗肾缺血再灌注损伤中的应用 - Google Patents
重组人髓源性生长因子在治疗肾缺血再灌注损伤中的应用 Download PDFInfo
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Abstract
本发明提供了重组人髓源性生长因子在用于制备治疗肾缺血再灌注损伤中的应用。本发明的重组人髓源性生长因子能够降低肾缺血再灌注损伤小鼠的血清肌酐和尿素氮水平，改善肾缺血再灌注损伤后的肾功能，具有肾脏保护作用同时能够减轻肾缺血再灌注损伤造成的氧化应激损伤。本发明为改善肾移植患者生活质量，延长移植肾生存时间带来希望，同时对于其它组织器官缺血再灌注损伤的防治也具有一定深远的影响。
Description
技术领域
本发明属于医药技术领域，具体涉及重组人髓源性生长因子在用于制备治疗肾缺血再灌注损伤中的应用。
背景技术
1960年Jennings首先提出“缺血再灌注损伤(ischemia-reperfusion injury，IRI)”这一概念，即组织器官缺血后恢复血流供应不仅不能使其功能得到恢复、损伤的结构得到恢复，反而造成其功能障碍和结构破坏进一步加重的现象，该现象可在多种器官中发生。肾脏本身血供极为丰富，对缺血再灌注损伤十分敏感。
由于肾移植过程的特殊性，目前的供者主要为循环死亡(DCD)后的捐献者，肾脏在供者体内血液供应被切断后发生“热缺血”，在随后的储存期间，温度低至约4℃，发生“冷缺血”。待移植入受者体内后，移植肾经历开放后的再灌注过程，肾缺血再灌注损伤已经成为移植肾功能延迟恢复(DGF)、移植物排斥反应、移植物慢性功能障碍以及进行性间质纤维化的主要原因之一。DGF是已故供者肾移植后较常见的早期并发症之一，现有的研究表明DGF主要是IRI引起的缺血后急性肾小管坏死的结果；肾移植术后IRI后的炎症反应也会导致移植物的免疫原性增强；IRI也可能由于补体反应和Akt通路介导的内皮-血管内皮递质转化(EndMT)引起肾纤维化。
IRI的病理生理机制非常复杂，具体发生机制至今尚未阐明，但在其早期阶段，单核/巨噬细胞介导的非特异性炎症反应和活性氧(Reactive oxygen species,ROS)过度产生是加重IRI的重要因素之一。肾脏IRI损伤可改变人、小鼠和大鼠肾脏中凋亡相关蛋白的，增加Bax并降低Bcl-2。肾小管上皮细胞也可通过产生促炎细胞因子(例如，TNF-α、白细胞介-6[IL-6]、IL-1β、转化生长因子-β[TNF-β])和趋化因子(例如，单核细胞趋化蛋白-1[MCP-1])来促进肾IR损伤中的炎症反应。
因此，发现可特异性降低巨噬细胞活性、有效减少ROS的产生、快速控制IRI后炎症反应的医疗产品，对于快速控制IRI的有害影响并提高长期同种异体移植物存活率，进而降低DGF发生率、改善移植肾远期存活具有重要意义。
近年来关于肾缺血再灌注损伤的机制研究已取得了一定的进展，但迄今为止，其病理生理机制尚未完全阐明。目前，针对IRI的治疗主要集中在清除活性氧，减少炎症，促进细胞存活等方面。移植肾存储，缺血预处理和后处理，细胞治疗，药物治疗等均可作为减少肾IRI的干预措施。目前主要集中在以下几个方面：
1.物理疗法：
现已公认需尽可能缩短缺血时间，并尽早恢复移植肾的血流供应。实验数据表明与静态冷藏相比，通过机器灌注保存的DCD肾脏发生DGF的可能性更低。
在大鼠、猪、人类的临床试验结果中，均表明缺血预处理(Ischemic pre-conditioning，IPC)对肾移植后肾功能的早期恢复有益。而缺血后处理(Ischemic post-conditioning，IPoC)即为在再灌注开始时快速、间歇地中断血流，在肾IRI的动物模型中可观察到IPoC可减少再灌注后肾小管坏死情况，并提高SOD表达水平以及抑制细胞凋亡。
越来越多的实验表明低浓度CO有较强的细胞保护作用，可能是通过抗氧化、抗炎、抗凋亡、抗纤维化、抗血栓形成等发挥作用。据报道CO在肾缺血再灌注期间可通过激活Akt和p38/MAPK途径抑制凋亡。在大鼠肾移植模型的研究中发现体外高压混合CO和O2可成功保存大鼠移植肾24h。
2.细胞疗法：
采用细胞疗法来调节肾IRI过程目前已引起了大量研究者的兴趣。目前已有大量关于干细胞的研究，尤其以间充质干细胞(mesenchymal stem cells，MSC)、诱导多能干细胞以及其条件培养基、外泌体的研究较多，已发现其作用机制主要集中在抗氧化、抗炎、抗凋亡以及免疫调节方面。将同种异体脂肪干细胞注射到移植动脉中的动物试验表明，其对肾移植结果、移植肾功能改善和大鼠存活率可发挥有益影响，但也存在不良影响。目前影响干细胞应用于临床的主要问题在于干细胞的不良分化及其可能的致畸致瘤作用；另一方面则是注射的MSC的细胞存活率差，大部分在24小时内死亡。
3.蛋白疗法
目前针对肾脏IRI的药物开发主要集中在清除活性氧方面。大量动物实验表明，外源性SOD、维生素C、维生素E等对于心肌缺血再灌注损伤有明显的保护作用。
Vlachopanos等人在用促红细胞生成素预处理可预防啮齿动物的IRI这一动物试验基础上进行临床试验，发现大剂量重组人促红细胞生成素能够减少DGF患者的数量。Yang等人向再灌注溶液中加入螺旋B肽，在热缺血20分钟和冷缺血18小时后常温灌注猪肾，发现其可改善再灌注期间的肾血流量，氧耗和尿量，并减少肾组织的损伤。Suhan Zhou等人基于血管性血友病因子裂解酶(ADAMTS13)的重组蛋白在缺血性脑损伤与心肌IRI中的保护作用，在小鼠IRI损伤模型中发现rhADAMTS13预处理可减少IRI后的细胞凋亡和炎症，改善内皮功能障碍。
近年来，大量文献已证实肾缺血再灌注损伤这一过程涉及到了大量分子通路的改变，尤其是针对IRI的蛋白疗法，大多是通过各种经典通路来发挥肾脏的保护作用。
已有研究者证实，肾缺血再灌注2h后核因子κB(nuclear factor kappa-B，NF-κB)被大量激活，主要集中在肾小管上皮细胞内表达，从而引起细胞间黏附分子-1(intercellular cell adhesion molecule-1，ICAM-1)、肿瘤坏死因子α(tumor necrosisfactor-α，TNF-α)的表达，进而导致肾组织损伤。目前主要关注点在于干预NF-κB的激活途径及信号传导等环节，从而治疗RIRI。
研究发现肾脏IRI时磷脂酰肌醇-3-激酶(phosphoinositide-3kinase，PI3K)/蛋白激酶B(protein kinase B，PKB/Akt)信号通路被激活，其作用机制可能是通过上调Bcl-2、下调Cleaved-Caspase3从而发挥抗凋亡特性；同时PI3K/Akt通路的下游靶标核因子E2相关因子2(nuclear factor erythroid-2-related factor 2，Nrf2)是参与内源性抗氧化的主要调节因子，PI3K/Akt通路的激活也可以减轻IRI期间氧化应激的损伤。例如，丹参酮可抑制缺氧/复氧诱导的HK-2细胞凋亡，且PI3K/Akt抑制剂LY294002可减弱其对HK-2细胞Caspase-3活性的抑制。
因此，研究肾缺血再灌注损伤这一病理生理过程中的关键分子及其作用机制，并在此基础上应用蛋白制品，对于临床防治肾缺血再灌注损伤具有重大意义。
发明内容
本发明的目的在于提供重组人髓源性生长因子在用于制备治疗肾缺血再灌注损伤的组合物中的应用。
本发明的另一目的是在于提供重组人髓源性生长因子在用于制备改善人近曲小管上皮细胞株缺血再灌注损伤的组合物中的应用。
本发明的重组人髓源性生长因子的蛋白序列如下：
MAAPSGGWNGVGASLWAALLLGAVALRPAEAVSEPTTVAFDVRPGGVVHSFSHNVGPGDKYTCMFTYASQGGTNEQWQMSLGTSEDHQHFTCTIWRPQGKSYLYFTQFKAEVRGAEIEYAMAYSKAAFERESDVPLKTEEFEVTKTAVAHRPGAFKAELSKLVIVAKASRTEL。
本发明的一种治疗肾缺血再灌注损伤的组合物，其特征在于，所述的组合物是以重组人髓源性生长因子作为唯一活性成分，或以包含重组人髓源性生长因子的药物组合物作为活性成分。
本发明的有益效果：本发明的重组人髓源性生长因子能够降低肾缺血再灌注损伤小鼠的血清肌酐和尿素氮水平，改善肾缺血再灌注损伤后的肾功能，具有肾脏保护作用同时能够减轻肾缺血再灌注损伤造成的氧化应激损伤。本发明为改善肾移植患者生活质量，延长移植肾生存时间带来希望，同时对于其它组织器官缺血再灌注损伤的防治也具有一定深远的影响。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例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，还可以根据这些附图获得其他的附图。
图1为各组小鼠血清肌酐(Cr)和尿素氮(BUN)水平；(A)血清肌酐；(B)尿素氮；
图2为各组小鼠SOD、GSH-PX和MDA水平；(a)SOD；(b)MDA；(c)GSH-PX；
图3为肿瘤坏死因子a(TNF-a)、白细胞介素6(IL-6)、白细胞介1β(IL-1β)mRNA的表达水平；(a)TNF-a；(b)IL-6；(c)IL-1β；
图4为Bcl-2及BAX的蛋白水平；
图5为肾小管上皮细胞的损伤程度；
图6为TUNEL阳性细胞所占的比例；
图7为P-Akt及Akt的蛋白水平。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。通常在此处附图中描述和示出的本发明实施例的组件可以以各种不同的配置来布置和设计。
因此，以下对在附图中提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施例。基于本发明中的实施例，本领域普通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。
本实施例的目的是探究重组人髓源性生长因子(rhMYDGF)对肾缺血再灌注损伤的保护作用。并揭示rhMYDGF在肾缺血再灌注损伤保护作用的机制，为临床研究提供理论依据。
1.重组人髓源性生长因子(rhMYDGF)rhMYDGF对肾脏缺血再灌注损伤的保护作用
(1)利用C57BL/6小鼠肾脏缺血再灌注模型检测rhMYDGF对肾脏缺血再灌注损伤的保护作用；
(2)检测模型鼠缺血再灌注后各项生化指标，揭示rhMYDGF对肾脏缺血再灌注损伤保护作用的机制。
2rhMYDGF对人近曲小管上皮细胞株(HK-2)的保护作用
(1)体外模拟缺血再灌注条件检测rhMYDGF对HK-2抗缺血再灌注损伤的保护作用；
(2)在分子水平上研究rhMYDGF对HK-2抗缺血再灌注损伤的保护作用机制。
肾缺血再灌注损伤模型建立：
(1)实验分组：6-8周龄C57BL/6小鼠术前12h禁食，自由进水，戊巴比妥钠(30mg/kg)腹腔注射麻醉后，沿腹正中线切开腹腔，分离左肾蒂并予以切除，同样的方法暴露右肾动、静脉，无损血管夹夹闭肾动脉，实验分为5组，每组8只C57BL/6小鼠，第一组：对照组，仅行左肾切除，右肾蒂游离。第二组：假手术组，右肾蒂钳夹时间35min；第三组：术前腹腔注射rhMYDGF 1.25ug/只，60min后行左肾切除，右肾动脉夹闭35min；第四组：术前腹腔注射rhMYDGF2.5ug/只,60min后行左肾切除，右肾动脉夹闭35min；第五组：术前腹腔注射rhMYDGF 5.0ug/只，60min后行左肾切除，右肾动脉夹闭35min。手术完成后，予以麻醉复苏，再灌注24h后取材。
(2)取材：24h后眼眶取血，室温放置30分钟后予以离心(4℃，3200rpm,10min)，收集血清；从左室灌注生理盐水并摘除右肾，一分为二，一部分液氮速冻，另一部分使用4％多聚甲醛过夜固定。
(3)检测指标：
1)各组肾功能的检测：血液经离心后取血清测定血清肌酐(Cr)和尿素氮(BUN)，发现术前腹腔注射rhMYDGF 1.25ug/只组小鼠的Cr和BUN均有明显改善(如图1所示)。
2)肾组织中氧化应激指标的检测：利用试剂盒检测肾组织匀浆中的丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)的活性，实验结果表明发现术前腹腔注射rhMYDGF 1.25ug/只组小鼠的氧化应激情况得到了明显得改善(如图2所示)。
3)各组肾组织炎症因子mRNA水平的检测：利用实时定量逆转录酶聚合酶链反应(RT-qPCR)法测定肾组织内肿瘤坏死因子a(TNF-a)、白细胞介素6(IL-6)、白细胞介1β(IL-1β)mRNA的表达水平(如图3所示)。
4)各组肾组织凋亡指标的检测：提取肾组织蛋白，利用Western Blot进行Bcl-2及BAX的蛋白水平检测，并利用Image J进行定量(如图4所示)。
5)肾脏组织形态学观察：组织经4％多聚甲醛固定后，石蜡包埋，进行HE及PAS染色，在普通光学显微镜下观察，其标准依据Jablonski评分方法定量肾小管上皮细胞的损伤程度(如图5所示)。
6)TUNEL染色及其定量分析：在光学显微镜400倍下每张切片随机选择5个视野，用Image J软件测量TUNEL阳性细胞所占的比例(如图6所示)。
7)检测各组肾组织蛋白中Akt通路情况：提取肾组织蛋白，利用Western Blot进行P-Akt及Akt的蛋白水平检测，并利用Image J进行定量(如图7所示)。
体外模拟缺血再灌注条件检测rhMYDGF对HK-2抗缺血再灌注损伤的保护作用
(1)CCK8法检测rhMYDGF对HK-2的抗缺血再灌注的保护作用：HK-2细胞以5X104/ml密度100μl/孔接种于96孔板培养过夜。细胞分为3组，包括空白对照组，缺氧/复氧模型组、缺氧/复氧+rhMYDGF预处理24h组。24小时后PBS洗涤细胞两次后，加入无血清无葡萄糖的DMEM培养基，并将种有后两组细胞的96孔板放入1％O2的低氧工作站中体外模拟缺血缺氧条件处理12h，然后放入常氧细胞培养箱中模拟体外复氧过程处理6h后每孔加入10ulCCK8溶液继续培养2h。在酶标仪OD450nm处测量各孔的吸光值。
(2)WesternBlot揭示rhMYDGF对HK-2抗缺血再灌注能力的分子机制：HK-2培养至对数生长期，细胞分组同CCK8法，每组加入相应的蛋白及抑制剂。37℃培养后收集细胞，加入RIPA裂解液，细胞质蛋白行10％SDS-PAGE分析后，转印于PVDF膜上，检测与细胞凋亡相关的Bcl-2及BAX的蛋白表达水平，以及Akt通路的激活情况。
(3)RT-qPCR揭示rhMYDGF对HK-2抗缺血再灌注能力的分子机制：HK-2培养至对数生长期，细胞分组同CCK8法。收集细胞，Trizol裂解液裂解细胞，提取细胞RNA后，检测与细胞炎症相关的TNF-a、IL-6、IL-1β的mRNA表达水平。
(4)HK-2细胞中氧化应激指标的检测：利用试剂盒检测各组细胞匀浆中的MDA、SOD以及GSH-PX的活性。
结果
如图1所示，术前腹腔注射rhMYDGF 1.25ug/只及2.5ug/只可明显改善肾IRI后的肾功能，具有肾脏保护作用，且具有统计学意义。
如图2所示，术前腹腔注射rhMYDGF 1.25ug/只组小鼠的SOD、GSH-PX水平明显较IRI组升高，MDA水平明显较IRI组下降，且具有统计学意义。
如图3所示，术前腹腔注射rhMYDGF 1.25ug/只组小鼠的TNF-a、IL-6、IL-1βmRNA表达水平明显较IRI组降低，且具有统计学意义。
如图4所示，Western Blot证实rhMYDGF可减少凋亡，抗凋亡蛋白BCL-2表达水平明显升高，促凋亡蛋白BAX表达水平明显下降。
如图5所示，PAS染色证实rhMYDGF 1.25ug/只组对肾组织的保护作用最强，且具有统计学意义。
如图6所示，TUNEL染色结果显示rhMYDGF可明显减少TUNEL阳性细胞的比例，减少细胞凋亡，且具有统计学意义。
如图7所示，Western Blot证实IRI组p-Akt蛋白表达水平较Sham组下降，术前腹腔注射rhMYDGF组p-Akt蛋白表达水平较IRI组升高。
以上所述，仅用以说明本发明的技术方案而非限制，本领域普通技术人员对本发明的技术方案所做的其它修改或者等同替换，只要不脱离本发明技术方案的精神和范围，均应涵盖在本发明的权利要求范围当中。
Claims (4)
1.重组人髓源性生长因子在用于制备治疗肾缺血再灌注损伤的组合物中的应用。
2.重组人髓源性生长因子在用于制备改善人近曲小管上皮细胞株缺血再灌注损伤的组合物中的应用。
3.根据权利要求1或2所述的重组人髓源性生长因子的蛋白序列如下：
MAAPSGGWNGVGASLWAALLLGAVALRPAEAVSEPTTVAFDVRPGGVVHSFSHNVGPGDKYTCMFTYASQGGTNEQWQMSLGTSEDHQHFTCTIWRPQGKSYLYFTQFKAEVRGAEIEYAMAYSKAAFERESDVPLKTEEFEVTKTAVAHRPGAFKAELSKLVIVAKASRTEL。
4.一种治疗肾缺血再灌注损伤的组合物，其特征在于，所述的组合物是以重组人髓源性生长因子作为唯一活性成分，或以包含重组人髓源性生长因子的药物组合物作为活性成分。
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| WO2024052564A1 (en) * | 2022-09-08 | 2024-03-14 | Boehringer Ingelheim International Gmbh | Myeloid-derived growth factor for use in treating cardiogenic shock |
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