再论急性高原肺水肿家族易感性问题（跟踪一家族在40年里祖孙三代病例摘要）

高原肺水肿家族易感性问题在世界范围内尚属探讨过程.作者曾于1987年第三届国际高原医学大会(日本.松本)报告了五个家庭20例病例的家族易感性问题.病例均在两代人或同代人身上发生,对其中一个家族在长达40年的追踪中发现祖孙三代人共6例先后发生12次急性高原肺水肿.其父亲在1968年首次乘机进藏既患急性高原肺水肿,经抢救治愈.在之后往返拉萨、成都20余次之中,还有两次发生肺水肿,既是乘机进藏在翻越海拔5000米的雀儿山时也发生肺水肿.在其余的进藏中由于采取预防措施及进藏立即吸氧,也有轻度症状发生,但未达到肺水肿的病情.其两儿一女均在乘机首次进藏后发生急性高原肺水肿.其中一人患过三次,另两人各一次.其孙辈:一人曾发生三次肺水肿, 另一人的女儿也发生一次肺水肿.在本家族中其母亲多次进出藏均未发生病,只有父亲、儿子、女儿和孙子及外孙相继发生肺水肿.在遗传学上肯定可以得到答案,有关DNA研究部门已着手进行研究,待后将公布于众.本文重点从临床角度对这一罕见家族易感病例作出报告.据此可以推断 ,高原肺水肿有家族易感性.     

急性高原病患者血浆肾素—血管紧张素—醛固酮系统及脑脊液变化

急性高原病通常分为急性高原反应(HAAR)、高原肺水肿(HAPE)和高原昏迷(HACC)三型。对其发病机理目前还存在着争议,为进一步探讨其发病机理,采用自身对比实验,观察了HAAR、HAPE各20名患者发病时及治愈后的血浆肾素(PRA)-血管紧张素(AⅡ)-醛固酮(ALD)系统及脑脊液变化。     

定量蛋白质组学在急性高原病研究中的应用进展

急性高原病(acute mountain sickness,AMS)是人体急性暴露于高原低压低氧环境后出现多系统生理紊乱的临床综合征。定量蛋白质组学技术可以系统定量并描述机体蛋白质组成和动态变化规律,近年来在多种疾病的预防、诊断、治疗和发生机制等方面研究应用广泛。本文系统综述了定量蛋白质组学技术及其在AMS的预防、诊断、治疗和急进高原习服机制研究中的应用进展,以期为AMS的发病机制、提前干预、临床治疗和AMS的蛋白质组学研究提供参考。     

传染性疾病的遗传易感性

传染性疾病是威胁人类健康的主要疾病类型之一。传染病的发生、发展是致病微生物、宿主的遗传因素与环境相互作用的结果。大量以单核苷酸多态性（SNP）为遗传标记,基于家系或无关群体的连锁和关联分析,已绘制出传染性疾病易感性的基因图谱。目前易感性的研究主要集中在疟疾、获得性免疫缺陷综合征、乙肝和严重急性呼吸系统综合征等传染性疾病。     

急性低氧对藏族长期移居海平后动脉血气的影响

本工作目的是研究长期移居海平后的藏族人回到高原后功能变化。研究对象是16名年轻藏族人,来上海(海平)前,均出生并居住于西藏高原(海拔高度约3700m),在上海上学4年期间从未返回高原。同时选取10名海平年轻汉族人作对照。观察急性低氧至3700m 2h后动脉血气的变化。动脉血气的各项指标用ABL3型血气分析仪自动测定。在经受3700m急性减压低氧后,长期移居海平藏族人的Pao_2和Sao_2明显高于海平汉族,分别为7.2±0.6,5.5±0.2kPa(P<0.05)和87.9±3.3％,78.2±1.6％(P<0.05)。长期移居海平后藏族人的Paco_2仍低于汉族人,而pH值高于海平汉族人,藏族人Hb含量低于海平汉族。研究结果提示,藏族人在低氧高原环境生长和发育过程中所形成的低氧适应能力可能是由藏族人遗传因素所决定的。     

慢性高原低氧对高原鼠兔和大鼠肝脏的作用

我们曾经发现,移入高原的实验大鼠子一代和高原鼠兔(Ochotona curzoniae)对高原低气压低氧有完全不同的适应能力和适应机理(杜继曾等,1982)。我们还观察到,在24小时急性高原低氧时,由低地移入2300米高原的大鼠后裔在5000米和8000米的高度上,出现了以转氨酶、肝溶酶体酸性磷酸酶活力升高、肝糖原和蛋白质含量下降的肝脏代谢异常和肝脏病理变化,而高原鼠兔只是在8000米高度时,才始出现部分指标的轻度变异(杜继曾等,1982),从而揭示了高原鼠兔的肝细胞代谢在细胞水平上对低氧的适应机制优越于移入高原的实验大鼠后代。慢性低氧又如何作用于大鼠和高原鼠兔的肝脏代谢?迄今尚无人研究。因此对这一作用规律的认识和阐明,在环境适应生理学领域、人类高原活动和畜牧业生产上都是十分重要的。     

单次高原运动对人体氧化压力的影响

为探讨高原与平原的单次有氧耐力运动对人体造成的氧化压力影响,本研究招募健康研究对象38位,其中男性20位,女性18位,通过随机交叉方式在高原与平原环境进行耐力运动,分析其安静(Pre)、运动后即刻(Post)以及运动后(10 min, 60 min, 120 min, 240 min)的血液生化指标。结果显示,血球积压(hematocrit, Hct)、乳酸(lactate)、尿酸(uric acid)与葡萄糖(glucose)浓度,在环境主要效果上的差异显著:高原环境显著高于平原环境(p0.05)。与在平原从事耐力运动者比较,高原耐力运动者运动后的血浆总蛋白、蛋白质羰基(PC)、硫代巴比妥酸反应物(TBARS)、氮氧化物(NO_x)浓度、超氧离子歧化酶(SOD)及过氧化氢酶(CAT)活性无显著性差异(p0.05)。本研究结果表明急性高原(2 400 m)耐力运动可能不会造成氧化压力,但会增加代谢压力。     

塔里木河叶尔羌高原鳅盐碱耐受性研究

采用急性毒理试验方法对塔里木河中叶尔羌高原鳅Triplophysa(Hedinichthys)yarkandensis(Day)分别在不同盐、碱度下进行了盐、碱耐受性试验,分析盐、碱胁迫对叶尔羌高原鳅毒性影响。结果显示:p H6.5~7.5,水温(20±1)℃,盐度对叶尔羌高原鳅12 h、24 h、48 h、72 h、96 h的半致死浓度分别为15.490 0‰、13.979 0‰、12.920 0‰、12.117 0‰、10.770 0‰,安全值为3.785 2‰;碱度对叶尔羌高原鳅12 h、24 h、48 h、72 h、96 h的半致死浓度分别为6.551 6 g·L~(-1)、5.164 5 g·L~(-1)、4.004 7 g·L~(-1)、3.601 7 g·L~(-1)、2.952 4 g·L~(-1),安全值为0.931 6 g·L~(-1)。研究表明,塔里木河水盐碱化严重影响了叶尔羌高原鳅的生长和发育,造成其资源锐减。本研究旨在为叶尔羌高原鳅驯化养殖和苗种培育提供科学依据。     

高原人红细胞乳酸脱氢酶同工酶的研究

人在高原,其组织在较低的氧分压下为了高效率地利用氧,必将会动员体内各种适应机制。红细胞增加使机体载氧能力加强就是其中之一。过去研究报道表明,在高山低氧和急性低氧条件下,人或动物体内乳酸脱氢酶(LDH)同工酶活性均有不同程度增高,关于高原低氧适应中红细胞LDH同工酶变化的研究,国内外报道尚少。本研究主要了解高原人红细胞LDH同工酶的变化。     

高原鼠兔下丘脑促肾上腺皮质激素释放因子的放射免疫测定

高原鼠兔已被我们选定为研究高原低氧适应机制的模型动物。我们过去的研究从器官水平乃至细胞和亚细胞水平均已证明该动物对高原低氧是不敏感的,属于高原低氧完全适应型动物。在研究下丘脑神经肽对高原低氧神经内分泌系的调控作用时,我们用大 鼠下丘脑促肾上腺皮质激素释放因子(Corticotropin releasing factor,CRF)的抗原、抗体放射免疫方法测定高原鼠免下丘脑CRF水平,获得了满意的结果,其灵敏度范围为3—200微微克/管,批间和批内变异系数分别为2.69％和7.24％。高原鼠兔下丘脑正中隆起处(Median eminence,ME)的提取物等的稀释液显示出与合成的大鼠CRF及其抗体间放射免疫反应的标准曲线,有很好的平行关系。高原鼠兔和大鼠ME处CRF的水平用此法测定分别为10.13±3.05和17.22±3.88微微克/毫克蛋白。大鼠ME处CRF水平随模拟海拔高度的增加而降低,而高原鼠兔不变化。随着肾上腺双侧切除,下丘脑ME之CRF下降,血浆皮质酮水平急剧下降,本结果提示,高原鼠兔的下丘脑确实含有与大鼠相类似结构与组成的CRF。此测定方法的确立,为研究高原鼠兔低氧神经内分泌适应机理,开拓了新路。     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.     

High Altitude Medical Problems

Increased travel to high altitude areas by mountaineers and nonclimbing tourists has emphasized the clinical problems associated with rapid ascent. Acute mountain sickness affects most sojourners at elevations above 10,000 feet. Symptoms are usually worse on the second or third day after arrival. Gradual ascent, spending one to three days at an intermediate altitude, and the use of acetazolamide (Diamox) will prevent or ameliorate symptoms in most instances. Serious and potentially fatal problems, such as high altitude pulmonary edema or cerebral edema, occur in approximately 0.5 percent to 1.0 percent of visitors to elevations above 10,000 feet—especially with heavy physical exertion on arrival, such as climbing or skiing. Early recognition, high flow oxygen therapy and prompt descent are crucially important in management. Our knowledge of the causes of these and other high altitude problems, such as retinal hemorrhage, systemic edema and pulmonary hypertension, is still incomplete. Even less is known of the effect of high altitudes on medical conditions common at sea level or on the action of commonly used drugs.     

Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.     

Contact phase of blood coagulation is not activated in edema of high altitude

To examine whether bradykinin generated by the activation of the contact phase of blood coagulation is involved in the pathogenesis of edema occurring after acute exposure to high altitude, 15 mountaineers were examined at 490 m and 1, 3, and 5 days after arrival at 4,559 m. The clotting activity levels of factor XII, factor XI, plasma prekallikrein, and high-molecular-weight kininogen (HMWK) were measured, and plasma kallikrein-induced proteolytic cleavage of HMWK was assessed by ligand blotting by use of radiolabeled factor XI. After an ascent on foot from 1,170 to 4,559 m in 3 days, three subjects developed high-altitude pulmonary edema, and four subjects presented facial edema. There was no evidence for activation of the contact system in any subject as demonstrated by the lack of proteolytic cleavage of HMWK at high altitude. The absence of contact system activation was further supported by stable plasma levels of the individual factors of contact activation. Therefore, we conclude that bradykinin generated by plasma kallikrein-induced cleavage of HMWK is not involved in the pathogenesis of edema due to acute exposure to high altitude.     

急性高原病的预防性用药

急性高原病是暴露于高原时,因高原低氧而在数小时至数天内出现的临床症候群,若不及时诊治,会发展为较为严重的高原肺水肿和高原脑水肿。随着我国对西部地区投入力度的增加,内地人员进入高原地区日渐增多,因此如何保证进入高原的人员健康,是医药科研工作的一项重要任务。为使人们有效快速地预防急性高原病,本文对国内外使用较为普遍的药物以及它们的作用机制进行了概述;并对有良好应用前景的药物进行了介绍。     

实验性高原肺水肿发病机制的初步研究

本研究用Ｗｉｓｔａｒ大鼠在模拟海拔６０００ｍ高度停留４８ｈ,对实验性高原肺水肿的发病机制进行了初步观察,结果表明：（１）大鼠肺血管外含水量明显增多;（２）肺泡隔增宽,肺泡隔内血管口径大小不一,有的扩张,有的狭窄甚至闭锁,硝酸镧示踪电镜术发现肺泡上皮、血管内皮和肺泡隔内有数量不等的镧颗粒;（３）硝苯啶或地塞米松均可使肺血管外含水量明显降低,二者联合作用效果更佳;（４）血浆内心钠素（ＡＮＰ）含量明显增多,伴有体重和血液含水量明显减少。从而表明,低氧性肺动脉压升高和肺泡壁微血管壁通透性增强在高原肺水肿的发生中有重要作用。血浆ＡＮＰ增加和伴随的血液浓缩是对抗血浆进一步外渗的因素之一。     

Evidence supportive of impaired myocardial blood flow reserve at high altitude in subjects developing high-altitude pulmonary edema

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.     

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.     

Platelet count and function at high altitude and in high-altitude pulmonary edema.

Platelet aggregation is the key process in primary hemostasis. Certain conditions such as hypoxia may induce platelet aggregation and lead to platelet sequestration primarily in the pulmonary microcirculation. We investigated the influence of high-altitude exposure on platelet function as part of a larger study on 30 subjects with a history of high-altitude pulmonary edema (HAPE) and 10 healthy controls. All participants were studied in the evening and the next morning at low altitude (450 m) and after an ascent to high altitude (4,559 m). Platelet count, platelet aggregation (platelet function analyzer PFA100; using epinephrine and ADP as activators), plasma soluble P (sP)-selectin, and the coagulation parameters prothrombin fragments 1+2 and thrombin-antithrombin complex were measured. High-altitude exposure decreased the platelet count, shortened the platelet function analyzer closure time by approximately 20%, indicating increased platelet aggregation, increased sP-selectin levels to approximately 250%, but left plasma coagulation unaffected. The HAPE-susceptible subjects were prophylactically treated with either tadalafil (a phosphodiesterase 5 inhibitor), dexamethasone, or placebo in a double-blind way. Subgroup analyses between these different treatments and comparisons of the seven placebo-treated individuals developing HAPE and controls revealed no differences in platelet count, platelet aggregation, or sP-selectin values. We conclude that exposure to high altitude activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. These effects are, however, not more pronounced in individuals with a history of HAPE or actually suffering from HAPE than in controls and therefore may not be a pathophysiological mechanism of HAPE.