高原病分子水平发病机制研究现状

高原病是发生于高原缺氧环境下的一种特发性疾病,当人进入高原地区时,机体因为环境的改变,会发生代谢失调,出现一系列的"高原反应",严重者可发生"高原病",从而危害人类健康甚至威胁生命。全世界有超过14 000万人居住在高原地区,因此对于高原病的发病机制研究极其重要,该文就高原病分子水平发病机制进行初步论述,为高原病的防治提供依据。     

缺氧诱导因子1与缺氧性肺动脉高压的研究进展

缺氧诱导因子1（HIF-1）是在缺氧条件下,广泛存在于哺乳动物和人体内的重要的转录调节因子.对低氧时组织细胞的信号转导起着重要的中介作用,通过对缺氧反应基因在转录水平的调节,从而使机体对缺氧刺激作出适应性的病理生理反应.HIF-1通过影响缺氧性肺血管收缩、肺血管重建、炎症发生及细胞凋亡等过程,参与缺氧性肺动脉高压（PHP）的形成.国内外学者通过对HIF-1与HPH相关性的探索和研究为临床HPH的治疗提供了一个新靶点.     

神经营养剂联合治疗新生儿缺氧缺血性脑病疗效观察

目的观察神经生长因子（NGF）和神经节苷脂（GM1）联合应用对中重度新生儿缺氧缺血性脑病（HIE）的疗效。方法将足月儿中重度新生儿缺氧缺血性脑病患儿150例随机分为NGF治疗组、GM1治疗组、NGF与GM1合用治疗组,观察比较3组临床疗效。结果合用组总有效率为96%,后遗症发生率为6%;NGF组总有效率为82%,后遗症发生率为22%;GM1组总有效率为84%,后遗症发生率为20%,合用组总有效率、后遗症发生率分别与NGF组、GM1组比较差异均有统计学意义（P〈0.05）。结论神经生长因子联合神经节苷脂对中重度新生儿缺氧缺血性脑病具有协同治疗作用,可提高早期治疗效果,减少后遗症的发生,值得临床推广应用。     

高原缺氧腹泻大鼠血清内毒素变化及其肝功能改变的相关性研究

目的:探讨模拟急进高原缺氧环境对大鼠血清内毒素(endotoxin)水平的影响及与肝功能损害的相关性。方法:将30只雄性Wistar大鼠均分为高原缺氧组和高原腹泻组,每组15只。高原组在平原饲养1个月后于24h内急运至海拔4767米高原,建立高原缺氧模型分别于到达高原后7d取门静脉血和腹主动脉血,分别检测各组间血LPS和肝功能(ALT、AST、TBil)。结果:与高原缺氧组比较,高原腹泻组血中LPS和ALT、AST、TBil均有明显升高(P均<0.01);高原腹泻组LPS升高与ALT、AST、TBil水平呈显著正相关(P<0.05)。结论:高原缺氧环境中,腹泻可加重肠黏膜屏障破坏,可导致肠源性内毒素血症,吸收入血的内毒素可能参与高原缺氧环境肝功能损害过程。     

低氧诱导因子1与脑出血的研究进展

低氧诱导因子1(HIF-1)是缺氧环境的重要调节因子,对低氧反应性基因的转录有调控作用,并参与低氧反应的信号转导过程。轻度缺氧时,HIF-1产生缺氧耐受性,发挥神经保护作用;长期重度缺氧时,诱导神经细胞凋亡,具有神经毒性作用。最近的研究表明,脑出血后随着局部脑血流量下降,HIF-1表达增加。现就HIF-1概况、低氧活性调节以及与脑出血的可能关系进行综述。     

高压氧对脑出血大鼠脑内HIF-1α表达和脑水肿的影响

目的探讨高压氧对血肿周边脑组织中HIF-1α蛋白表达和脑水肿程度的影响。方法 SD大鼠88只随机分为假手术对照组(sham组,8只)、脑出血组(ICH组)和脑出血+高压氧治疗组(HBO治疗组)。ICH组和HBO治疗组又分为6h组、24h组、3d组、7d组和14d组,每组8只。采用自体血脑内注射法建立脑出血动物模型,干湿比重法测定脑组织含水量,以免疫组化的方法检测血肿周边脑组织中HIF-1α蛋白表达情况,同时观察高压氧对脑水肿和HIF-1α表达的影响。结果 ICH组和HBO治疗组与sham组比较,脑组织含水量明显增加,差异有统计学意义(P<0.05)。HBO治疗组与ICH组大鼠脑组织含水量第14天时比较差异有统计学意义(P<0.05)。与sham组比较,ICH组和HBO治疗组HIF-1α表达明显增加,差异有统计学意义(P<0.05)。HBO治疗组与ICH组大鼠脑组织中HIF-1α表达第14天时比较,差异有统计学意义(P<0.05)。ICH组HIF-1α蛋白表达与脑水肿的程度成正相关(P<0.01);HBO治疗组HIF-1α蛋白表达与脑水肿的程度无相关性(P>0.05)。结论 HIF-1α在血肿周边脑组织中的表达与脑水肿的形成和发展有关,高压氧可抑制HIF-1α蛋白的表达并减轻脑水肿。     

Moderate altitude but not additional endurance training increases markers of oxidative stress in exhaled breath condensate

Oxidative stress occurs at altitude, and physical exertion might enhance this stress. In the present study, we investigated the combined effects of exercise and moderate altitude on redox balance in ten endurance exercising biathletes, and five sedentary volunteers during a 6-week-stay at 2,800 m. As a marker for oxidative stress, hydrogen peroxide (H₂O₂) was analyzed by the biosensor measuring system Ecocheck™, and 8-iso prostaglandin F2α (8-iso PGF2α) was determined by enzyme immunoassay in exhaled breath condensate (EBC). To determine the whole blood antioxidative capacity, we measured reduced glutathione (GSH) enzymatically using Ellman’s reagent. Exercising athletes and sedentary volunteers showed increased levels of oxidative markers at moderate altitude, contrary to our expectations; there was no difference between both groups. Therefore, all subjects’ data were pooled to examine the oxidative stress response exclusively due to altitude exposure. H₂O₂ levels increased at altitude and remained elevated for 3 days after returning to sea level (p ≤ 0.05). On the other hand, 8-iso PGF2α levels showed a tendency to increase at altitude, but declined immediately after returning to sea level (p ≤ 0.001). Hypoxic exposure during the first day at altitude resulted in elevated GSH levels (p ≤ 0.05), that decreased during prolonged sojourn at altitude (p ≤ 0.001). In conclusion, a stay at moderate altitude for up to 6 weeks increases markers of oxidative stress in EBC independent of additional endurance training. Notably, this oxidative stress is still detectable 3 days upon return to sea level.

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The contribution of Max Gassmann and Katja Heinicke who are the senior authors was equivalent.     

Attenuated phrenic long-term facilitation in orexin neuron-ablated mice

We examined phrenic long-term facilitation (LTF) in urethane-anesthetized, vagotomized, paralyzed, and artificially ventilated orexin neuron-ablated mice and their wild-type littermates. Effect of isocapnic single hypoxic episode (SHE, for 45 s) and intermittent hypoxia (IH, 5 times of SHE separated by 5 min) on phrenic nerve activity (PNA) was measured for 1–2 h. In wild-type mice, amplitude of PNA gradually increased after cessation of IH and reached 55 ± 15% above the baseline (n = 7, p < 0.05) whereas the burst rate of PNA did not change. Qualitatively similar but significantly attenuated response (16 ± 8%) was observed in orexin neuron-ablated mice. SHE did not affect amplitude nor frequency in both animals. We conclude that orexin contributes to eliciting phrenic LTF at least in part in mice. This study also showed, for the first time, phrenic LTF following IH in WT mice. Characteristics of phrenic and ventilatory LTF in mice were similar to those in rats.     

低氧对裸鼹鼠皮肤成纤维细胞自噬水平及凋亡的影响

目的 比较裸鼹鼠成纤维细胞常氧与低氧条件下自噬与凋亡水平.方法 分别采用低氧（3％O2）与常氧（20％ O2）培养裸鼹鼠皮肤成纤维细胞,采用Western blotting、RT-PCR等方法检测自噬相关基因Beclin1、LC3的表达,并用流式细胞术检测低氧与常氧条件下裸鼹鼠成纤维细胞凋亡水平.结果 裸鼹鼠皮肤成纤维细胞在低氧与常氧处理24 h时,LC3 Ⅱ蛋白的表达量并无明显差异,而低氧处理48 h后LC3 Ⅱ蛋白的表达量显著高于常氧组,并且裸鼹鼠成纤维细胞随着低氧培养时间的延长,LC3 Ⅱ蛋白表达升高.流式细胞术结果显现低氧处理组裸鼹鼠皮肤成纤维细胞凋亡率显著低于常氧组.结论 裸鼹鼠皮肤成纤维细胞可以通过提高自噬水平适应低氧环境,这为今后深入研究裸鼹鼠耐低氧机制提供了参考.     

低氧诱导的非酒精性脂肪性肝炎动物模型的构建

目的：构建低氧诱导的非酒精性脂肪性肝炎动物模型。方法50只大鼠分为正常组、低氧组、高脂组、低氧高脂组4组,分别给予正常饮食、腹腔内注射亚硝酸钠、高脂饮食、腹腔内注射亚硝酸钠＋高脂饮食。检测4组大鼠生化指标（ALT、AST、AKP、TG）、透明质酸（HA）、动脉高铁血红蛋白及氧分压,并行肝组织HE与Masson染色及NASH评分。结果低氧高脂组大鼠的ALT、AST、AKP、TG、HA明显升高,NASH评分明显增加,肝组织可见明显的脂肪变性、炎症细胞浸润及纤维化。结论高脂饮食大鼠诱导单纯脂肪肝基础上给予腹腔注射亚硝酸钠能够建立低氧诱导的非酒精性脂肪性肝炎动物模型。