摘要
高原一般指海拔高于3000米的地区,急性高原缺氧会引起明显的胃肠反应,急进高原人员最常见的早期反应是胃肠道症状,恶心、呕吐、食欲减退、腹胀、腹部不适或隐痛可高达60%以上,有文献报道,4000米以上高原急性缺氧环境下消化性溃疡出血率达63.1%,其中大出血占55%,溃疡复发为67%,溃疡穿孔达到25.6%,可见急性高原缺氧会对机体胃肠消化系统造成严重损伤。尽管如此,国内外对于如何预防或降低高原急性缺氧造成的肠粘膜及肠组织损伤的研究却并不多见。
牛磺酸是体内一种游离的条件必需氨基酸,广泛分布于机体各个组织细胞中,特别是在骨骼肌、神经、腺体等可兴奋组织内含量更高。大量研究证明,牛磺酸具有保护心血管系统、调节神经系统、促进消化吸收及解毒等广泛的生理、药理活性,同时牛磺酸在体内还具有细胞保护作用,能够抗氧化及清除过量自由基、稳定细胞膜、保持细胞内Ca~(2+)稳定等。研究表明,牛磺酸对于高原急性缺氧造成的脑损伤和视网膜损伤具有显著的保护作用,能降低血小板聚集、拮抗兴奋性氨基酸的神经毒性、具有调节Ca~(2+)稳态的作用、减少一氧化氮(NO)和自由基产生、抗脂质过氧化、降低组织缺血中细胞凋亡的发生及影响缺氧诱导因子的表达,但牛磺酸对于高原急性缺氧造成的肠黏膜、肠组织损伤是否具有保护作用,国内外尚未见报道。
小肠粘膜上皮组织是机体吸收营养物质的主要场所,同时也是抵御病菌入侵的重要屏障,对于机体能量代谢和各项生理功能的维持具有重要作用。小肠粘膜上皮组织代谢非常旺盛,血液中氧的水平及弥散入组织的氧浓度,对维持肠粘膜上皮细胞的各种正常代谢起着非常重要的作用,缺氧可对肠粘膜组织造成严重的损伤,因此保护和减轻高原急性缺氧对小肠黏膜组织的损伤对于预防高原反应至关重要。缺氧诱导因子(hypoxia-inducible factor,HIF)是缺氧条件下广泛存在于哺乳动物及人体的一种转录因子,是机体缺氧适应性反应所需要的核信号,对于机体在缺氧过程中的适应性反应具有核心作用,是机体耐受缺氧、保持氧稳态的重要因素。缺氧诱导因子-1(HIF-1)是由两个蛋白质亚基(HIF-1α、HIF-1β)组成的二聚体转录因子,在细胞缺血、缺氧时,HIF-1产生并处于缺氧应答的关键环节,通过调控其下游靶基因的转录、表达,促进机体对缺氧产生一系列的适应反应,这是目前研究比较明确的缺氧诱导基因转录和缺氧信息传递的共同通路,由于HIF-1在其中起关键作用,因此被称为缺氧适应调节的管家转录因子。急性高原缺氧会引起明显的葡萄糖吸收、代谢异常,严重时甚至会引起能量衰竭。机体血糖水平对高原急性缺氧极为敏感,急性缺氧会使机体血糖水平明显降低,影响机体正常能量代谢和各项机能。葡萄糖转运蛋白(glucose transports,GLUTs)是体内负责葡萄糖吸收、转运的重要蛋白质,特别是GLUT2和GLUT5,是小肠组织中负责葡萄糖吸收、转运的载体。我们推测,牛磺酸可能能有效减轻高原急性缺氧造成的肠组织损伤,保护小肠黏膜组织,促进高原急性缺氧条件下机体对葡萄糖的吸收、转运,而其中机制可能在于牛磺酸能够提高HIF-1及GLUTs的表达,加快和增强机体对高原急性缺氧条件的适应。
基于以上分析,本研究运用低压氧舱模拟4500m和5500m两个不同高度急性高原缺氧环境,并在多个时相点进行观测,采用组织病理学、透射电镜、RT-PCR、Westernblotting等实验技术方法,观察高原急性缺氧条件下大鼠小肠粘膜组织损伤及血清葡萄糖水平变化,同时利用牛磺酸进行膳食干预,观察牛磺酸对高原急性缺氧造成的小肠组织损伤的防护作用,并从HIF-1及GLUTs方面探讨其分子机制。
主要实验结果如下
1.通过组织病理学和透射电镜技术对小肠粘膜上皮细胞形态结构及超微结构的观察结果表明,高原急性缺氧可造成小肠粘膜上皮细胞水肿、出血,肠绒毛排列紊乱、大量脱落,超微结构观察可见线粒体肿胀、内质网扩张、细胞结构紊乱等细胞损伤,而牛磺酸膳食干预可明显减轻其损伤状况,无论在绒毛排列、水肿、脱落等方面,还是在细胞微绒毛形态,线粒体、内质网结构以及胞内状况等方面均有明显减轻,表明牛磺酸对高原急性缺氧造成的肠粘膜上皮细胞损伤具有明显的防护作用。
2.RT-PCR和Western blotting的检测结果表明,高原急性缺氧条件下,大鼠小肠组织中HIF-1α、HIF-1β的表达水平明显增强,并在缺氧12 h左右达到峰值,随后逐渐减弱;同时结果还表明,添加一定剂量牛磺酸组HIF-1α、HIF-1β在各时相点的表达水平相对于未加牛磺酸组均有所增强,并在缺氧2h或6h后表现出显著性差异,表明牛磺酸能够显著增强高原急性缺氧大鼠小肠组织HIF-1α和HIF-1β的表达。
3.大鼠血清葡萄糖水平及小肠组织GLUT2、GLUT5表达水平的检测结果表明,高原急性缺氧条件下大鼠血清葡萄糖水平明显下降,小肠组织中GLUT2、GLUT5的表达水平显著降低,但添加牛磺酸组血清葡萄糖水平及小肠组织中GLUT2、GLUT5的表达水平均明显高于相应对照组,表明,牛磺酸能够显著抑制高原急性缺氧造成的血清葡萄糖水平及小肠组织GLUT2、GLUT5表达的下降。
综上所述,本课题研究结果表明,牛磺酸对于高原急性缺氧造成的小肠组织损伤具有明显的防护作用,能够有效减轻高原急性缺氧条件下小肠黏膜上皮细胞损伤状况,抑制血清葡萄糖水平的下降,而其中机制可能在于牛磺酸能够显著增强缺氧条件下小肠组织中HIF-1α、HIF-1β的表达水平,从而增强缺氧信号的传导,通过调控其下游靶基因的转录、表达,如增强GLUT2、GLUT5的表达,提高机体对高原急性缺氧的适应能力。
In high altitude area over 3 000 meters,hypobaric hypoxia can lead to obvious indisposition of stomach intestine such as nausea,vomit,decreased appetite,abdominal distention,vague pain et ct.Some studies report that acutely advancing to plateau over 4 000m,occurrence of hemorrhage of peptic ulcer would be 63.1%,hemorrhea would be 55%, recurrence of ulcer would be 67%and perforation would be 25.6%.It is thus evident that high altitude hypoxia can cause serious injury to gastrointestinal digestion;however,there is a deficiency in studies how to protect intestinal mucosa and intestines tissue from hypobaric hypoxia damage.
Taurine,one of sulfur amino acids and conditional essential amino acids,wide exists in various tissue of body especially in excitable tissues of muscle,nervous system, glandular organ.Studies suggest taurine is multifunctional agent of protecting cardiovascular system,modulating nervous system,promoting digestion and detoxication. Furthermore,taurine possesses cytoprotection activities and is notable to act as an antioxidant,membrane and Ca~(2+) stabilizing agent.Researches indicated taurine could significantly prevent brain and retina injury from hypobaric hypoxia through decreasing platelet aggregation,inhibiting neurotoxicity of excitatory amino acids,modulating stabilization of Ca~(2+),reducing synthesis of NO and free radical,resisting lipid peroxidation, inhibiting apoptosis and enhancing expression of hypoxia inducible factor.However, whether taurine could protect intestinal mucous membrane and intestinal tissue from hypobaric hypoxia damage is not clear,there is a lack in this field.
Intestinal mucous epithelial tissue is the place to absorb nourishments for the body and it is also an important barrier for resisting invasion of bacteria.Therefore,it plays a role in energy metabolism and various physiologic functions.The metabolism of intestinal mucous epithelial tissue is high,oxygen concentration in blood and organization is essential to maintain various physiological processes of intestinal mucous cells.Hypobaric hypoxia could lead to serious damage to intestinal mucous epithelial tissue;therefore it is necessary to search effective way to relieve intestine injury caused by hypobaric hypoxia for precaution from high altitude reaction.Hypoxia-inducible factor is a kind of transcription factor which wild exists in mammals and human being and expresses in anoxia condition. Hypoxia-inducible factor is the necessary nuclear signal for the organism response of adaptation reaction to hypobaric hypoxia;it plays a key role in these processes. Hypoxia-inducible factor-1(HIF-1),consisted of two protein subunits HIF-1αand HIF-1β,would bring out when cells in ischemic or hypoxia conditions and exert critical effect on adaptation reaction;it can promote a serial of adaptive responses to oxygen deficiency by means of regulating the transcription and expression of down stream target genes.This is the conclusive and common molecular mechanism of hypoxia-induced genes transcription and hypoxia signal conduction.Considering to the critical role in the adaptive response to hypoxia,HIF-1 is called housekeeper transcription factor of hypoxia regulation.
Acute high altitude hypoxia can cause serious absorb and metabolism dysfunction of glucose,even lead to energy exhaustion.The blood sugar level of body is extremely sensitive to the hypobaric hypoxia.Hypobaric hypoxia can significantly decrease the blood sugar level,impact the normal energy metabolism and function of the body.Glucose transports(GLUTs) are important proteins in charge of absorbing and transporting glucose in the body.GLUT2 and GLUT5 are vehicles in the intestine tissue to absorb and transport glucose.Therefore,the expression and modulation of GLUT2 and GLUT5 play an essential role in the process of glucose absorb and metabolism in the body.Based on the analysis above,we presume taurine maybe an effective protective agent of intestine tissue damage induced by hypoxia.Taurine could significantly protect intestinal mucous membrane, promote the absorption and transport of glucose,the mechanism of the effect involves increasing expression of HIF-1 and GLUTs,enhancing the body adaptive response to hypoxia.
The purpose of this study was to determine whether taurine could protect intestine tissue from hypoxia induced rat intestine tissue damage and the associated molecular mechanism.A rat model was used to simulate 4 500 meters or 5 500 meters high altitude hypoxia conditions in low-pressure chamber and observations were taken in many phase points.Immunohistochemistry,transmission electron microscope,RT-PCR and western blotting method were used to study the structural and functional damage of the intestine tissue induced by acute continuous hypoxia,also as the proective effects of taurine and the associated molecular mechanism concerned with HIF-1 and GLUTs.
The main results and conclusions were summarized as follows:
1.The observation results of immunohistochemistry and transmission electron microscope to the morphous,structure and ultrastructure of intestine mucous epithelial cells suggested acute hypobaric hypoxia could induce serious structural and functional damage to the intestine mucous epithelial cells,symptoms including cellularedema,hemorrhage, disorder and defluxion of intestinal villus.Ultramicrostructural observation showed a series of cellular damages including intumesces of the chondriosome,distension of endocytoplasmic reticulum,disorder of the cellular structure.Taurine nutritional treatment could significantly relieve the intestine mucous epithelial cells damage induced by hypobaric hypoxia according to the state of intestinal villus,cellularedema,hemorrhage and the structure of the microvillus,chondriosome,endocytoplasmic reticulum and other inner cellular conditions.
2.Results of RT-PCR and western blotting showed in the hypobaric hypoxia condition the expression of HIF-1αand HIF-1βin intestine tissue of rats significantly increased and reached the peak after 12h,then gradually decreased.Taurine nutritional treatment could significantly promote the expression of HIF-1αand HIF-1βin intestine tissue of rats in hypobaric hypoxia condition.
3.In the hypobaric hypoxia condition,the serum glucose level and the expression of GLUT2 and GLUT5 in intestine tissue of rats significantly decreased.Taurine nutritional treatment could effectively inhibit the decrease of the serum glucose level and the expression of GLUT2 and GLUT5 induced by hypobaric hypoxia.
Above all,the study suggested taurine nutritional treatment could effectively relieve the intestine tissue damage induced by acute hypobaric hypoxia and significantly extenuate the intestinal mucous epithelial cells injury,and inhibit the decrease of the serum glucose level.The mechanism of effects maybe associated with the fact that taurine could promote the expression of HIF-1α,HIF-1β,GLUT2 and GLUT5 in intestine tissue of rats in the hypobaric hypoxia condition,enhance the ability of adaptive response to hypoxia and glucose absorption and transport.
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