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Background -The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose ofthis study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. Methods -The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-la, IL-1p, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-a, and the soluble form of Pselectin. Results -At admission there were significant increases in the levels oftotal cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals.Furthermore, the levels of IL-1p, , and TNF-a were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-la, IL-10, and P-selectin did not change. Conclusions -These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid. (Thorax 1996;51:739-742) Keywords: cytokines, bronchoalveolar lavage, high altitude pulmonary oedema.High altitude pulmonary oedema (HAPE) is a non-cardiogenic pulmonary oedema that occurs in healthy individuals and is seen among those ascending above 2700 m in the Japanese Alps.' Its precise mechanism remains unresolved. Although the oedema formation of HAPE might be related to the shear forces associated with increased pulmonary vascular pressure," it is mainly due to increased pulmonary permeability.4 Conversely, recent studies5-7 of the pathophysiology of adult (or acute) respiratory distress syndrome (ARDS) or acute lung injury, a pulmonary oedema with typically increasing permeability, have revealed that ARDS is characterised by a significant inflammatory component followed by infiltration of mainly neutrophils and macrophages. There are many studies of chemical mediators, chemical cytokines, and adhesion molecules in the bronchoalveolar lavage (BAL) fluid of patients with ARDS.5-7 Sakamaki et al have recently reported that the level of the soluble form of P-selectin is increased in the plasma of patients with ARDS. From its clinical characteristics it is possible that HAPE is one form of acute lung injury, but no data are available concerning these mediators in HAPE. We have measured the levels of chemotactic cytokines and Pselectin in the BAL fluid ofpatients with HAPE in order to evaluate the role of these mediators in the development of HAPE. Methods PATIENTSWe examined the cellular and biochemical markers and the chemical cytokines in the BAL fluid of four men with HAPE who were admitted to Shinshu University Hospital (600 m above sea level) which is located at the foot of the Japanese Alps. Al...

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)

E En nd do ot th he el li in n--1 1 a an nd d i in nt te er rl le eu uk ki in n--8 8 i in n h hi ig gh h a al lt ti it tu ud deABSTRACT: We present a case of high altitude pulmonary oedema (HAPE) with pulmonary hypertension and polymorphoneuclear leucocyte (PMN) accumulation in bronchoalveolar lavage fluid (BALF), which occurred in a 21 year old man. Plasma endothelin-1 (ET-1) and interleukin-8 (IL-8) concentration in BALF were elevated on admission, and returned to normal level at recovery, when the pulmonary artery pressure and the PMN counts in BALF were normal. In addition, E-selectin and intercellular adhesion molecule-1 (ICAM-1) in BALF were also slightly increased on admission.These findings suggest that endothelin-1 is a vasoconstrictor which contributes to the pulmonary hypertension in high altitude pulmonary oedema, and that some of the inflammatory mediators play an important role in chemotaxis and accumulation of polymorphonuclear leucocytes in the development of high altitude pulmonary oedema. Eur Respir J., 1996Respir J., , 9, 1947Respir J., -1949. High altitude pulmonary oedema (HAPE) is a severe type of acute mountain sickness. It is a serious, sometimes fatal illness related to rapid exposure to altitude. Although the pathophysiological mechanism of HAPE remains unclear, it has long been suggested that pulmonary vasoconstriction and increased pulmonary vascular permeability are important contributory factors [1,2]. Recent studies have suggested that endothelin is related to pulmonary vasoconstriction [3][4][5], and that the increased pulmonary vascular permeability is probably caused by inflammatory mediators [6][7][8][9][10]. However, no studies have been conducted on the role of endothelin and cytokines in patients with HAPE. We report a case of HAPE, documenting the possible role of endothelin-1 (ET-1), and polymorphoneuclear leucocyte (PMN) chemotactic mediators, such as interleukin-8 (IL-8). Case reportA Japanese male university student, aged 21 yrs, who was healthy before climbing, arrived at the foot of the Japan Alps at 1,000 m above sea level. The next morning, he started climbing to a snowy valley about 2,000 m above sea level and still felt well. On the third day, whilst climbing to Mt Yari (3,180 m), he developed general fatigue, followed by headache, cough, sputum, poor appetite and fever (38˚C). After staying all day to rest at 3,000 m, his condition progressively deteriorated. On the fifth day, he was lethargic, comatose, cyanotic, and had a cough with foamy sputum. He was rescued, transported by helicopter, and admitted to our Shinshu University Hospital (660 m).On admission, he had cyanosis and was unconscious. His temperature was 38˚C, pulse rate 140 beats·min -1 , respiration rate 26 breaths·min -1 , and his blood pressure 140/90 mmHg. Coarse crackles were audible over both sides of the lung. He showed decerebrate rigidity. An examination of the ocular fundi showed papilloedema and multiple flame-shaped and blot haemorrhages in both fundi. A chest roentgenogram revealed patc...

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