花岡正幸

(日本信州大學(xué)醫(yī)學(xué)院第一醫(yī)學(xué)部 ，呼吸性疾病、感染性疾病和過敏性疾病學(xué)部，日本 松本 390-8621)

1 Introduction

Highland is a low-oxygen environment，and alveolar hypoxia caused by reduced inhalation oxygen partial pressure induces various physiological changes in the body.When a human rapidly reaches high altitude，acclimation of the body including the cardiorespiratory system occurs to adapt with the environment，but dysadaptation occurs and acute mountain sickness develops in some individuals.High-altitude pulmonary edema(HAPE)is the severest form of acute mountain sickness，and it is prototype pulmonary edema induced in healthy individuals by hypoxia，low pressure，exercise load，and coldness.

2 Clinical features of HAPE[1，2]

HAPE is noncardiogenic pulmonary edema developing in healthy individuals within 48～96 hours after rapidly reaching high altitude.It is often complicated by high-altitude cerebral edema and progresses to a serious state，resulting in death when rescue is delayed.In Japan，most patients are climbers，and a few cases occur yearly.On the other hand，people going to high altitude in foreign countries for sightseeing and trekking have increased and unexpected accidents due to this disease have been reported.In Japan，HAPE frequently occurs in the central mountainous region centering the Northern Alps，but almost no case occurs in single peaks，such as Mt.Fuji.The altitude for disease development ranges from 2 350(Akadakekousen)to 3 190 m(Mt.Okuhotakatake)in Japan.The mean age of patients is about 40 years old and the incidence is high in males.Recurrent cases are occasionally noted and account for about 20% of all cases.The initial symptoms are severe malaise，dyspnea during body movement，unsteady steps，and extreme reduction of walking speed.Fever and dry cough accompany in many cases，being confused as cold.Dyspnea aggravates as pulmonary edema progresses，and wheezing and pink-colored foamy sputum accompany.Disturbance of consciousness is observed in about 2/3 of cases，and severe cases fall in stupor/coma.These symptoms aggravate at night in many cases.Regarding physical findings，tachycardia，tachypnea，and cyanosis are observed，and rales(coarse crackles)are audible in the chest.On arterial blood gas analysis，severe hypoxemia and respiratory alkalosis are observed.On chest radiography，infiltrative shadows asymmetrically scattering in the bilateral lung fields are the characteristic finding，and it is accompanied by dilation of the pulmonary artery trunk.On chest CT，many patchy shadows are heterogeneously distributed from the pulmonary hilum，but diversity has been clarified.In cases complicated with high-altitude cerebral edema，reductions of the density in the white matter and size of the ventricles by exclusion are observed on brain CT.The diagnostic criteria of HAPE established by Hultgren et al.[3]is widely used(Table 1)，and it is important to make differential diagnosis from pneumonia and congestive heart failure.

Table 1Diagnostic criteria of high-altitude pulmonary edema

Note：Cited and modified from Reference[3].

3 Pathophysiology of HAPE

Pulmonary arterial pressure and pulmonary vascular resistance increase in hemodynamics of HAPE in the acute phase，but the pulmonary arterial wedge pressure and cardiac index are within the normal ranges.The hemodynamics rapidly normalizes as the clinical symptoms are improved by treatment，i.e.，pulmonary hypertension is involved in the pathology of HAPE and this pulmonary hypertension is noncardiogenic and reversible.

In bronchoalveolar lavage(BAL)in the acute phase，the total number of cells，especially neutrophils，increases and the levels of inflammatory cytokines，such as interleukin(IL)-1，IL-6，IL-8，and tumor necrosis factor(TNF)-α，markedly increase[4，5].These increases in cytokines are also transient and normalized with improvement of the clinical symptoms，suggesting involvement of inflammation in development or progression of HAPE.

In the autopsied lung，the alveoli filled with exudate，hyaline membrane formation，inflammatory cell infiltration，and dilation and congestion of capillary blood vessels were observed[6].On immunostaining，loss of surfactant，fusion and degeneration of type II alveolar epithelial cells，and accumulation of mast cells were observed.[6]

4 Constitutional predisposition for HAPE

In academic climbing(Nakabusa Hot Spring- Mt.Tsubakurodake- Mt.Daitenjodake)by subjects with previous history of HAPE performed in 1986，percutaneous arterial oxygen saturation(SpO2)significantly decreased in the subjects with previous history of HAPE compared with that in healthy subjects without history of HAPE，and the acute mountain sickness score was significantly higher in the subjects with history of HAPE than the subjects without history of HAPE.In addition，one subject with previous HAPE actually developed HAPE.

In a study conducted in Matsumoto City(610m above the sea level)，a low oxygen load induced marked increases in pulmonary arterial pressure and pulmonary vascular resistance in subjects with previous history of HAPE and it was accompanied by hypoxemia[7].Similar reactions were also induced by a low pressure and exercise load[7].In addition，low oxygen load-induced redistribution of pulmonary blood flow toward the pulmonary apex was observed in subjects with previous HAPE on lung ventilation-perfusion scintigraphy[8]，suggesting that strong hypoxic pulmonary vasoconstriction(HPV)of arterioles in the basal part of the lung caused pulmonary hypertension and redistribution of pulmonary blood flow.These specific reactions in pulmonary circulation are understood as constitutional predisposition for HAPE，so-called susceptibility.

5 Molecular-genetic analysis of HAPE

5.1 Endothelial nitric oxide synthase(eNOS)gene

“Impairment of NO synthesis” is attracting attention as a cause of severe HPV.Inhalation of NO decreased pulmonary arterial pressure，improving oxygenation，in HAPE patients.[9]NO in expired gas clearly decreased in a high-altitude environment in subjects with previous HAPE and a significant inverse correlation with pulmonary arterial pressure was noted[10].Thus，we investigated Glu298Asp mutation(glutamic acid at position 298 is substituted by aspartic acid)and intron 4b/a polymorphism(27-basepair repeated structure in the 4th intron)in theeNOSgene in subjects with previous HAPE and healthy climbers.The frequencies of the Asp allele of Glu298Asp mutation andeNOS4aof intron 4b/a polymorphism were significantly higher in the subjects with previous HAPE[11].In addition，the presence of both Asp allele andeNOS4awas detected only in subjects with previous HAPE[11]，suggesting thateNOSgene mutation impaired NO synthesis in the high-altitude environment and induced severe pulmonary hypertension.It was also suggested that theeNOSgene polymorphisms may serve as a useful marker to detect the susceptible individuals to HAPE.

5.2 Comprehensive gene analysis

Comprehensive gene analysis using microsatellite markers was performed in subjects with previous history of HAPE and healthy climbers without history of HAPE.Eight genes were identified near the microsatellite marker showing a significant difference[12]，and the most powerful significance was in the gene of tissue inhibitor of metalloproteinase 3(TIMP3).Confirmation analysis was performed using 6 single nucleotide polymorphisms(SNP)in theTIMP3 gene，and a significant difference was detected in one SNP[12]between the two groups.TIMP3 antagonizes matrix metalloproteinase(MMP)and the balance between these is considered important for maintenance of homeostasis of the lung parenchyma.Comprehensive gene analysis suggested that theTIMP3 gene is also involved in development of HAPE.

6 Pathogenesis of HAPE

In individuals witheNOSgene mutation，impairment of NO synthesis induces severe HPV in a hypoxic environment and causes pulmonary hypertension.In pulmonary capillary vessels with local internal pressure elevation(over perfusion)，strong “shear stress” is loaded on vascular endothelium，which collapses the alveolar-capillary barrier and red blood cells and plasma protein unidirectionally leak into the alveolar space[13].This hypothesis known as “stress failure” was demonstrated by analysis of BAL fluid in the early phase of HAPE by Swenson et al. in 2002[14]clarifying that the origin of this disease is “hydrostatic pressure pulmonary edema”.In advanced stage of HAPE，the number of neutrophils and protein and inflammatory cytokine levels in BAL fluid increase，showing “permeability pulmonary edema”[4，5].Therefore，it was clarified that the essence of HAPE is “mixed pulmonary edema” which advances from “hydrostatic pressure pulmonary edema” to “permeability pulmonary edema”.

7 Conclusion

HAPE is “mixed pulmonary edema” which develops in a high-altitude “hypobaric and hypoxic environment”.Investigation of its pathophysiology and individual susceptibility leads to elucidation of the pathology of many diseases manifesting hypoxia and pulmonary circulatory disorder as the main characters.Japan has played the major role in the field of high-altitude medical science and further advancement in research is expected.