CN111514281A - 饥饿素联合l-丝氨酸复方对脓毒症的治疗作用 - Google Patents
饥饿素联合l-丝氨酸复方对脓毒症的治疗作用 Download PDFInfo
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Abstract
本发明公开了饥饿素联合L‑丝氨酸复方对脓毒症的治疗作用，从在体及离体两个水平展开，在体动物模型实验采用盲肠结扎穿刺的小鼠脓毒症模型CLP，离体实验采用小鼠的小肠、肝脏和脾脏对应的原代细胞，拟观察假手术组、盲肠结扎穿刺组及盲肠结扎穿刺并给予外源饥饿素条件下，各组织/细胞内铁代谢相关蛋白表达变化，激活或阻断GHSR1a受体、MAPK（ErK1/2）信号通路后铁代谢相关蛋白的表达和细胞铁含量的变化，并监测小鼠血清铁含量、红细胞生成及组织铁含量的变化，验证Ghrelin/GHSR1a/MAPK在盲肠结扎穿孔模型下参与调控机体各组织间铁动员，增加血清铁、降低铁调素及促进血红蛋白合成，最终减轻脓毒症贫血及组织缺氧损伤。
Description
技术领域
本发明涉及饥饿素与L-丝氨酸复方的应用技术领域，尤其涉及饥饿素联合L-丝氨酸复方对脓毒症的治疗作用。
背景技术
脓毒症是指机体对感染反应失调所致的危及生命的器官功能障碍(Singer M,Deutschman CS,Seymour CW,et al.The third international consensus definitionsfor sepsis and septic shock(Sepsis-3)[J].JAMA,2016,315(8):801-810.)。脓毒症可由多种病因引起,主要表现为血液中炎性介质的持续高浓度存在,重者可导致多器官功能衰竭而危及生命。
脓毒症相关性脑病(sepsis-associated encephalopathy，SAE)是由脓毒症引起的脑功能障碍。(Zhang LN,Wang XT,Ai YH,et al.Epidemiological features and riskfactors of sepsis-associated encephalopathy in intensive care unit patients:2008-2011[J].Chin Med J(Engl)2012,125(5):828-831.)SAE病情从谵妄到深昏迷，以行为、认知、觉醒和意识改变为特征，且相当比例的患者存在长期认知功能障等。脓毒症患者的中枢神经系统和血液中无细菌入侵，仍可发生脑功能障碍，其发生是由于感染引起机体产生全身炎症反应并作用于大脑，从而导致脑内炎性反应、微循环、血脑屏障及神经递质传递异常等所致。(Berg RM,
Bailey DM.Neuro-oxidative-nitrosative stressinsepsis[J].JCereb Blood Flow Metab,2011,31(7):1532-1544.)70％的脓毒症患者具有从嗜睡到昏迷等不同程度的神经系统症状，超过80％的患者存在脑电图异常。SAE是ICU中最常见脑病。(唐会,罗丹,纪木火,杨建军.脓毒症相关性脑病的研究进展[J].临床麻醉学杂志,2016,32(07):717-720.)
抑制过度的炎症反应是控制脓毒症相关性脑病进展的一个关键措施。L-丝氨酸是一种重要的胶质细胞源性神经物质，对神经元存活及神经突起的生长有重要作用。L-丝氨酸在脑内分布广泛，大脑皮质、海马、胼胝体、小脑皮质及脑干部位均有不同程度的表达(Yasuda E,Ma N,Semba R.Immunohistochemical demonstration of L-serinedistribution in the rat brain.Neuroreport,2001,17,12(5):1027-1030)。同时L-丝氨酸作为一种抑制性氨基酸，脑损伤后使用可逆转兴奋性氨基酸/抑制性氨基酸比例失调，激活脑内的甘氨酸受体，从而拮抗或抑制谷氨酸的兴奋性神经毒性(Wang GH,Jiang ZL,ChenZQ,et al.Neuroprotective effect of L-serine against temporary cerebralischemia in rats.J Neurosci Res,2010,88(9):2035-2045)。我们的实验结果发现，L-丝氨酸治疗可以抑制脱髓鞘损伤，改善小鼠空间学习及记忆能力，缓解焦虑情绪；L-丝氨酸对白质损伤的治疗作用可能与抑制炎症反应、促进少突胶质细胞增生有关。
脓毒症可同时导致脓毒症相关性贫血(Soares MP,Hamza I.Macrophages andIron Metabolism.Immunity.2016 Mar15；44(3):492-504.PubMed PMID:26982356.PubmedCentral PMCID:4794998)。脓毒症患者入住ICU后大多进食差或需鼻饲，常发生营养不良，而营养不良又可降低免疫力，加重感染。同时，炎症可导致患者肠黏膜受损，营养素(尤其是铁)吸收减少。研究表明，75％的脓毒症ICU危重症患者会发生缺铁(Bateman AP,McArdleF,Walsh TS.Time course of anemia during six months follow up followingintensive car edischarge and factors associated with impaired recovery oferythropoiesis.Critical care medicine.2009 Jun；37(6):1906-12.PubMed PMID:19384207)。脓毒症相关性贫血发生率仅次于缺铁性贫血，被称为“慢性病贫血”。由于患者的医源性失血、血浆铁降低、促红细胞生成素产生受抑制及红细胞寿命缩短、营养不良等原因，贫血成为脓毒症的常见特征且可能使病情复杂化。入住ICU3天内贫血发生率可高达90％以上，且贫血程度会随住院时间的延长而加重。因脓毒症贫血治疗一直备受关注。
近年来研究发现饥饿素在脓毒症动物模型中有较好的治疗作用，发现在盲肠结扎穿的大鼠脓毒症模型5小时后饥饿素表达显著降低，给与饥饿素后可改善血液动力学、增加心输出量、减弱脓毒症模型大鼠炎症反应、下调血浆及组织中促炎介质的释放、器官损伤和降低死亡率(Wang W,Bansal S,Falk S,Ljubanovic D,Schrier R.Ghrelin protectsmice against endotoxemia-induced acute kidney injury.American journal ofphysiology Renal physiology.2009 Oct；297(4):F1032-7.PubMed PMID:19625378)。据此我们推测脓毒症导致内源性饥饿素表达降低，铁调素表达增高。通过提高脓毒症患者血清饥饿素可促进Ghrelin/GOAT/GHSR1a/MAPK系统激活上调膜铁转运蛋白1表达，增加小肠饮食吸收铁、肝脏储存铁以及脾脏巨噬细胞回收铁的输出，从而加速机体组织铁的动员。从而，一方面增加血清铁含量，降低血清铁调素含量，抑制脓毒症患者血清铁的持续下降，促进红细胞的生成。另一方面为红细胞的生成提供更多的铁。最终缓解脓毒症患者的贫血、组织缺氧和炎症情况。而L-丝氨酸是潜在性的甘氨酸受体激动剂，脑内含量丰富。在成年动物体内，甘氨酸受体的活化会诱导Cl-内流和神经元超极化，从而降低神经元的兴奋性；甘氨酸受体的活化可能通过抵消脑卒中时神经元的去极化而对抗谷氨酸的兴奋性毒性作用，以及之后导致细胞死亡的生物化学级联反应。另外一方面，L-丝氨酸是中枢神经系统重要的一种非必需氨基酸，为合成磷脂酰丝氨酸、鞘脂、核苷酸及神经递质D-丝氨酸的前体；也是一种重要的胶质细胞源性神经营养因子，对神经元存活及神经突起的生长有重要作用20。L-丝氨酸及其代谢产物不仅为细胞增殖所需，在中枢神经系统中它还有特殊的功能，为脑的发育和许多正常功能所需。
脓毒症具有高发病率和高死亡率的特点。脓毒症的治疗强调综合治疗，包括多脏器支持治疗、抗炎治疗，液体复苏等治疗方法。因为病理生理机制方面的研究进展较少，脓毒症的治疗也没有取得较大的突破。本发明首次使用L-丝氨酸与饥饿素联合治疗脓毒症脑病以及脓毒症贫血，为临床治疗脓毒症提供策略，发现具有很重要的实用价值。
脓毒症治疗花费高，医疗资源消耗大，严重影响人类的生活质量，已经对人类健康造成巨大威胁。
发明内容
本发明提供饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，解决现有技术中的目前脓毒症的发病机制仍未完全阐明，且脓毒症的病理机制常常涉及全身多个系统，引起多器官功能损伤，单一的治疗方式不能取得良好的效果等技术问题。
本发明采用以下技术方案：饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，L-丝氨酸与饥饿素联用对脓毒症的治疗作用：从在体及离体两个水平展开，在体动物模型实验采用盲肠结扎穿刺的小鼠脓毒症模型CLP，离体实验采用小鼠的小肠、肝脏和脾脏对应的原代细胞，拟观察假手术组、盲肠结扎穿刺组及盲肠结扎穿刺并给予外源饥饿素条件下，各组织/细胞内铁代谢相关蛋白表达变化，激活或阻断GHSR1a受体、MAPK(ErK1/2)信号通路后铁代谢相关蛋白的表达和细胞铁含量的变化，并监测小鼠血清铁含量、红细胞生成及组织铁含量的变化，验证Ghrelin/GHSR1a/MAPK在盲肠结扎穿孔模型下参与调控机体各组织间铁动员，增加血清铁、降低铁调素及促进血红蛋白合成，最终减轻脓毒症贫血及组织缺氧损伤。
作为本发明的一种优选技术方案：所述第一步中小肠、肝脏和脾脏对应的原代细胞具体为小肠上皮细胞、肝实质细胞和腹腔巨噬细胞。
作为本发明的一种优选技术方案：所述治疗组在手术半小时后给药，给药浓度即L-丝氨酸的浓度为342mg/kg。
作为本发明的一种优选技术方案：所述第二步中水合氯醛将小鼠麻醉中水合氯醛用量为10％水合氯醛，0.1ml/10g。
作为本发明的一种优选技术方案：所述第一步中组织/细胞内铁代谢相关蛋白表达变化监测方法为Western blot检测。
1、作为本发明的一种优选技术方案：所述第一步中激活或阻断GHSR1a受体监测方法为通过加入GHSR1a受体激活剂或者阻断剂实现，通过检测下游信号通路观察是否有效。
作为本发明的一种优选技术方案：所述第一步中MAPK(ErK1/2)信号通路后铁代谢相关蛋白的表达变化监测方法为用Western blot检测。
作为本发明的一种优选技术方案：所述第一步中细胞铁含量的变化监测方法为细胞总铁测定法。
作为本发明的一种优选技术方案：所述第一步中小鼠血清铁含量、红细胞生成及组织铁含量的变化监测方法分别为：试剂盒检测、血常规、组织铁测定法。
有益效果：
本发明所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用采用以上技术方案与现有技术相比，具有以下技术效果：
1、采用L-丝氨酸与饥饿素联合治疗主要针对脓毒症引起的脓毒症贫血与脓毒症脑病在动物模型上取得了很好的治疗效果；
2、首次使用L-丝氨酸(内源性氨基酸)与饥饿素(内源性激素)联合治疗脓毒症脑病以及脓毒症贫血，为临床治疗脓毒症提供策略，发现具有很重要的实用价值；
3、饥饿素与L-丝氨酸复方制备为临床治疗脓毒症提供策略，尤其可以缓解脓毒症脑病以及脓毒症贫血；
4、如表1所示，饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠炎症反应；
5、如表2和表3所示，饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠血液凝血时间；
6、如表4所示，饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠血液继发性纤溶亢进；
7、如图1所示，饥饿素与L-丝氨酸复方治疗组能明显改善脓毒症小鼠血清学相关指标，增加血清铁、降低铁调素及促进血红蛋白合成，最终减轻脓毒症贫血及组织缺氧损伤；
8、如图2所示，饥饿素与L-丝氨酸复方治疗组能明显减轻脓毒症小鼠脑内炎症因子表达，减轻脓毒症脑病的发生。
附图说明
图1是实施例1盲肠结扎穿孔模型小鼠血清学相关指标的影响图。
图2是实施例2炎症因子表达图。
具体实施方式
以下结合实例对本发明作进一步的描述，实施例仅用于对本发明进行说明，并不构成对权利要求范围的限制，本领域技术人员可以想到的其他替代手段，均在本发明权利要求范围内。。
实施例1：
饥饿素对脓毒症的治疗作用，步骤为：
第一步，基础研究从在体及离体两个水平展开，在体动物模型实验采用盲肠结扎穿刺的小鼠脓毒症模型CLP；
第二步，离体实验采用小肠、肝脏和脾脏对应的原代细胞，具体为小肠上皮细胞、肝实质细胞和腹腔巨噬细胞，拟观察假手术组、盲肠结扎穿刺组及盲肠结扎穿刺并给予外源饥饿素条件下，各组织/细胞内铁代谢相关蛋白表达变化，激活或阻断GHSR1a受体、MAPK(ErK1/2)信号通路后铁代谢相关蛋白的表达和细胞铁含量的变化，并监测小鼠血清铁含量、红细胞生成及组织铁含量的变化。
验证Ghrelin/GHSR1a/MAPK在盲肠结扎穿孔模型下参与调控机体各组织间铁动员，增加血清铁、降低铁调素及促进血红蛋白合成，最终减轻脓毒症贫血及组织缺氧损伤。
如图1所示，*P＜0.05；**p<0.01，在盲肠结扎穿孔模型小鼠血清中饥饿素及酰化后的饥饿素含量在2天显著下降。同时血清铁、转铁蛋白饱和度显著降低，不饱和铁结合力升高。
如图1所示，*P＜0.05；**p<0.01，推测通过提高脓毒症患者血清饥饿素可促进Ghrelin/GOAT/GHSR1a/MAPK系统激活上调膜铁转运蛋白1表达，增加小肠饮食吸收铁、肝脏储存铁以及脾脏巨噬细胞回收铁的输出，从而加速机体组织铁的动员。从而，一方面增加血清铁含量，并降低血清铁调素含量，从而抑制脓毒症患者血清铁的持续下降，促进红细胞的生成。另一方面为红细胞的生成提供更多的铁。最终缓解脓毒症患者的贫血、组织缺氧和器官损伤等症状。
实施例2：
L-丝氨酸与饥饿素联用对脓毒症的治疗作用，步骤为：
第一步，采用的模型是小鼠脱髓鞘模型，通过向C57/BL6小鼠立体定位注射溶血卵磷脂LPC造成白质损伤，之后予以L-丝氨酸治疗，具体步骤如下：腹腔注射水合氯醛将小鼠麻醉，将其固定在脑立体定位仪上；
第二步，消毒并切开小鼠头皮，暴露前囟，读取前囟坐标；
第三步，确定胼胝体位置，在对应颅骨处开骨窗，移动立体定位仪垂直标尺，将微量进样器针头置于骨孔处，参照小鼠脑立体定位图谱确定胼胝体坐标，注射体积为1.5μL，注射速度为0.3μL/min，留针10min，缓慢退针；
第四步，缝合皮肤，术后将老鼠置于笼内正常饲养；
第五步：治疗组在手术半小时后给药，给药浓度即L-丝氨酸的浓度为342mg/kg，每天两次，连给5天。
实验结果如下：
(1)L-丝氨酸对炎症因子的影响
如图2所示，*P<0.05，**P<0.01，n＝n＝10，注射LPC后，小鼠胼胝体区IL1-β、TNF-α表达水平显著升高，经L-丝氨酸治疗后，两者的表达均受到抑制。
(2)L-丝氨酸与饥饿素联用对炎症因子的影响
表1：饥饿素与L-丝氨酸复方能明显抑制脓毒症小鼠炎症反应。
表2：饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠血液凝血时间；较脓毒症组相比，复方治疗组能显著降低血浆凝血酶时间和活化部分凝血活酶时间。
表3：饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠血液凝血时间；较脓毒症组相比，复方治疗组能显著降低血浆凝血酶原时间、增加纤维蛋白原时间。
表4：饥饿素与L-丝氨酸复方能明显改善脓毒症小鼠血液继发性纤溶亢进；较脓毒症组相比，复方治疗组能显著降低血浆纤溶酶原激活抑制剂和D-二聚体含量。
Claims (9)
1.饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：L-丝氨酸与饥饿素联用对脓毒症的治疗作用：从在体及离体两个水平展开，在体动物模型实验采用盲肠结扎穿刺的小鼠脓毒症模型CLP，离体实验采用小鼠的小肠、肝脏和脾脏对应的原代细胞，拟观察假手术组、盲肠结扎穿刺组及盲肠结扎穿刺并给予外源饥饿素条件下，各组织/细胞内铁代谢相关蛋白表达变化，激活或阻断GHSR1a受体、MAPK（ErK1/2）信号通路后铁代谢相关蛋白的表达和细胞铁含量的变化，并监测小鼠血清铁含量、红细胞生成及组织铁含量的变化，验证Ghrelin/GHSR1a/MAPK在盲肠结扎穿孔模型下参与调控机体各组织间铁动员，增加血清铁、降低铁调素及促进血红蛋白合成，最终减轻脓毒症贫血及组织缺氧损伤。
2.根据权利要求1所述的饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：所述第一步中小肠、肝脏和脾脏对应的原代细胞具体为小肠上皮细胞、肝实质细胞和腹腔巨噬细胞。
3.根据权利要求1所述的饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：所述治疗组在手术半小时后给药，给药浓度即L-丝氨酸的浓度为342 mg/kg。
4.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于，所述第二步中水合氯醛将小鼠麻醉中水合氯醛用量为10%水合氯醛，0.1ml/10g。
5.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于，所述第一步中组织/细胞内铁代谢相关蛋白表达变化监测方法为Western blot检测。
6.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于，所述第一步中激活或阻断GHSR1a受体监测方法为通过加入GHSR1a受体激活剂或者阻断剂实现，通过检测下游信号通路观察是否有效。
7.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：所述第一步中MAPK（ErK1/2）信号通路后铁代谢相关蛋白的表达变化监测方法为用Westernblot检测。
8.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：所述第一步中细胞铁含量的变化监测方法为细胞总铁测定法。
9.根据权利要求1所述饥饿素联合L-丝氨酸复方对脓毒症的治疗作用，其特征在于：所述第一步中小鼠血清铁含量、红细胞生成及组织铁含量的变化监测方法分别为：试剂盒检测、血常规、组织铁测定法。
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