When low‐altitude people rapidly ascend to altitudes above 2500 m, they run a risk of developing high‐altitude pulmonary edema (HAPE).1 The first scientific report in an English‐written journal was published in 1960,2 and still in 1975 the article by Kleiner and Nelson in JAMA had a title: High‐altitude pulmonary edema: A rare disease?3 However, as tourism at high altitudes has become common and as mountaineering has gained in popularity, HAPE has become a common threat. If not treated (by descent or by oxygen delivery), the condition is fatal, and probably added to the death toll of Mount Everest climbers, which was headline news last year.

The likelihood of suffering from HAPE increases with altitude and with the speed of ascending, but pronounced individual differences are observed.1, 4, 5 The exact reasons behind the susceptibility to HAPE are, as yet, not clear. Although not easily compatible with all aspects of what is known about circulation, the development of HAPE has been thought to have the following sequence of events: pulmonary hypertension results from a selective vasoconstriction of arterioles and is transmitted to capillaries with the consequence that their permeability increases and fluid with high‐molecular‐weight proteins and erythrocytes reaches alveoli.1, 4, 5 Also inflammation is usually observed, and although it is sometimes considered to be part of the development of HAPE, it is often considered to be secondary to oedema formation.1 From the above it is obvious that the detailed mechanisms of how HAPE develops are still unclear 60 years after its description, although the clinical picture of the condition is quite clear. The reason for the lack of understanding is largely that scientists have not been able to develop feasible animal models of HAPE.1, 5

Gojkovic et al6 have now developed a new mouse model, which shows most of the HAPE symptoms such as pulmonary oedema, reduced physical performance and increased permeability of lung vessels. Figure 1 gives the overall summary of what has been observed in the model. The outset was that HAPE is mainly a hypoxia response. Acute hypoxia responses are characterized by the stabilization of the hypoxia‐inducible transcription factor (HIF; both HIF1α and HIF2α) and the consecutive transcriptional induction of many genes.7, 8 Normally the stabilization of HIF1α and HIF2α requires hypoxia, but in the case of VHL protein deficiency also occurs in normoxia.9 Gojkovic et al6 made a mouse model in which the VHL protein of myeloid cells was conditionally deleted. They ascertained that HIF1α and HIF2α were stabilized in normoxia in the mouse phenotypes generated. Furthermore, they also showed that the pulmonary oedema generated was not cardiogenic, as little changes in cardiac function occurred, and the observed change (reduced stroke volume) would not be expected to cause oedema formation.

Interestingly, in addition to the common HAPE syndromes, pulmonary oedema, increased pulmonary vascular permeability, and reduced performance during exertion, the mice lacking VHL protein in pulmonary myeloid cells, also showed pulmonary inflammation. This suggests that inflammation may be a part of HAPE development, not merely its consequence. The result is reasonable, as HIF‐system is intimately involved in inflammation.10-12 The authors further evaluated transcriptional differences in pulmonary tissue between the myeloid VHL‐deficient and control mice. They noted that more than 400 genes were differentially transcribed in the two groups. About 90% of the cases had increased mRNA levels and 10% decreased. Concentrating on transcriptional differences is warranted, as HIFs are transcription factors. However, further studies are clearly required to assess, whether the transcriptional effects are also observed at the protein level, leading to functional effects. Still, many of the transcriptional changes fit with the functional effects: the reduced stroke volume, increased permeability of pulmonary vessels and inflammatory responses all have candidate genes among the differentially expressed transcripts between the myeloid VHL‐deficient and control mice.

As the authors conclude, ‘a deregulated myeloid cell hypoxic response can trigger some of the most important symptoms of HAPE and thus mice with a deletion of VHL in the myeloid lineage can function as a model of HAPE’. This model has the potential to be of great benefit for our understanding and treatment of HAPE.

当低海拔人员迅速上升到2500 m以上的高度时，他们就有发展为高海拔肺水肿（HAPE）的风险。1英文期刊的第一份科学报告于1960年发表，2直到1975年Kleiner和Nelson在JAMA上发表的文章标题为：高原肺水肿：一种罕见的疾病？3然而，随着高海拔旅游业的普及和登山运动的普及，HAPE已成为普遍的威胁。如果不进行治疗（通过下降或通过氧气输送），这种疾病将是致命的，并且可能增加珠穆朗玛峰登山者的死亡人数，这是去年的头条新闻。

HAPE患病的可能性随着海拔和上升速度的增加而增加，但是观察到明显的个体差异。1，4，5的易感性HAPE背后的确切原因，到目前为止，还不明确。尽管与血液循环的所有方面都不容易兼容，但是HAPE的发展被认为具有以下一系列事件：肺动脉高压是由小动脉的选择性血管收缩引起的，并传播至毛细血管，其通透性增加含有高分子量蛋白质和红细胞的液体进入肺泡。一四五通常还观察到炎症，尽管有时认为它是HAPE发生的一部分，但通常认为它是水肿形成的继发性疾病。1从上面显然的高原肺水肿如何发展的具体机制仍其描述60周年不清楚，虽然病情的临床表现是相当清楚的。缺乏了解的原因在很大程度上是因为科学家未能开发出可行的HAPE动物模型。1、5

Gojkovic等[ 6]现在已经开发了一种新的小鼠模型，该模型显示出大多数HAPE症状，例如肺水肿，身体机能下降和肺血管通透性增加。图1给出了模型中已观察到的总体摘要。开始时，HAPE主要是低氧反应。急性缺氧反应的特征在于低氧诱导型转录因子（HIF；HIF1α和HIF2α均）的稳定和许多基因的连续转录诱导。7，8通常情况下，稳定HIF1α和HIF2α需要缺氧，但在常氧状态下也会发生VHL蛋白质缺乏症。9 Gojkovic等人6制作了小鼠模型，其中有条件地删除了髓样细胞的VHL蛋白。他们确定在产生的小鼠表型中，HIF1α和HIF2α在常氧状态下稳定。此外，他们还表明，由于心功能发生的变化很小，因此产生的肺水肿不是心源性的，而且观察到的变化（卒中体积减少）也不会导致水肿的形成。

有趣的是，除了常见的HAPE综合征，肺水肿，肺血管通透性增加和运动过程中的表现降低外，肺髓样细胞中缺乏VHL蛋白的小鼠也表现出肺部炎症。这表明炎症可能是HAPE发展的一部分，而不仅仅是其后果。结果是合理的，因为HIF系统与炎症密切相关。10-12作者进一步评估了髓样VHL缺陷小鼠和对照组小鼠在肺组织中的转录差异。他们指出，两组中有400多个基因被差异转录。大约90％的病例的mRNA水平升高，而10％的病例降低。由于HIF是转录因子，因此必须专注于转录差异。但是，显然需要进一步的研究来评估是否还在蛋白质水平上观察到转录作用，从而导致功能作用。尽管如此，许多转录变化仍与功能作用相适应：中风量减少，肺血管通透性增加和炎症反应都在髓样VHL缺陷小鼠和对照小鼠之间差异表达的转录本中都有候选基因。

正如作者总结的那样，“失控的髓细胞低氧反应可以触发HAPE的一些最重要的症状，因此髓系中VHL缺失的小鼠可以作为HAPE的模型”。该模型对于我们对HAPE的理解和治疗具有巨大的潜力。