Yukinori Matsuzawa

Association of High-Altitude Pulmonary Edema With the Major Histocompatibility Complex

BACKGROUND A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects. METHODS AND RESULTS The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (P=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6-positive subjects with HAPE was significantly higher than that of the HLA-DR6-negative subjects with HAPE. CONCLUSIONS There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.

Effects of simulated high altitude on event-related potential (P300) and auditory brain-stem responses.

OBJECTIVE This study investigated the effect of hyobaric hypoxia on cognitive function. METHODS We recorded the auditory brain-stem response (ABR) and auditory-evoked event-related potentials (ERP) in 7 male subjects during a rapid ascent to a simulated 4500 m altitude from their acclimatized altitude of 610 m. The amplitude and latency of each component of ABR and of ERP were assessed. RESULTS Compared with the values at 610 m, at 4500 m the latencies of both waves I and V of ABR significantly increased, with no change in I-V interpeak latency; and the amplitude of wave I decreased, with no change in the amplitude of wave V. The increase in altitude affected neither the amplitude nor the latency of N100. The P300 latency was prolonged significantly after exposure to hypobaric-hypoxic conditions for 2h, with no significant change in amplitude. At 4500 m, the P300 latency returned to the baseline value after oxygen was inhaled. CONCLUSIONS Our results suggest it is possible to boost cognitive processing by supplying oxygen even when auditory stimulus intensity decreases under hypobaric and hypoxic conditions, and that P300 latency is affected by hypoxic more than hypobaric conditions. SIGNIFICANCE This study demonstrated that each component of ABR and the latency of both N100 and P300 are important to record when the effects of hypobaric hypoxia on cognitive function are investigated.

Plasma levels of atrial natriuretic peptide under acute hypoxia in normal subjects

To investigate whether the acute hypoxia can be a stimulus for atrial natriuretic peptide (ANP) secretion, plasma levels of ANP were determined under three different hypoxic conditions in six normal subjects. During 15% O2 breathing for 10 min, no significant change in plasma ANP level was observed. Severe hypoxia induced by 10% O2 breathing increased the mean pulmonary arterial pressure (Ppa) by 11.6 mm Hg within 10 min (P less than 0.01), accompanying a slight but significant rise in plasma ANP level of pulmonary artery (PA) from 24.3 +/- 5.3 to 28.2 +/- 4.6 pg/ml (P less than 0.05). There was a tendency for the ANP level of PA to rise under hypoxic hypobaria at 515 Torr for 10 min, followed by a decrease of that level during 100% O2 breathing under hypobaric condition. These changes, however, still remained in the normal range. No significant changes were observed both in right atrial pressure and in pulmonary capillary wedge pressure under any of the three hypoxic conditions. From these results we conclude that ANP can be released in response to the elevation of Ppa caused by acute hypoxia in normal subjects, but the changes in plasma ANP level may be too small to play a significant physiological role in hemodynamic responses to acute hypoxia.

Comparisons of oxygen transport between Tibetan and Han residents at moderate altitude

To compare the difference for oxygen transport between Tibetans living for generations at high altitude and acclimatized Han newcomers to high altitude, we measured the ventilatory, circulatory, metabolic, and gas exchange functions during exercise in 17 Tibetans and 19 Hans at the altitude of 3417 m. At maximal effort, the Tibetans, compared with the Hans, showed higher O 2 consumption ( V ˙ o 2 max ) (2.54±0.1 versus 2.10±0.1 liters min −1 , p p −1 , p P −1 ) was higher than that in the Hans (68.0±3.9 liters min −1 ), but the ventilatory equivalent was equal. The anaerobic threshold for absolute O 2 consumption ( V ˙ o 2 AT ) for the Tibetans and Hans was 1.91±0.1 versus 1.45±0.1 liters min −1 , respectively ( p 2 consumption (in % V ˙ o 2 max ) was 76.2±1.5 versus 70.5±2.2, respectively ( p V ˙ o 2 max correlated well with maximal cardiac output. No difference was found in the maximal heart rate between the two groups. Arterial oxygen desaturation from rest to exercise in the Hans (15.3%; 90.3–76.5%) was greater than that in the Tibetans (9.2%; 90.1–81.8%). We conclude that the lifelong exposure to an hypoxic environment has resulted in an increase in oxygen transport and improved aerobic exercise performance.

Neutrophil elastase inhibitor reduces asthmatic responses in allergic sheep

To determine the role of neutrophil elastase in asthmatic responses, we studied the effect of ONO-5046, a specific neutrophil elastase inhibitor, on antigen-induced asthmatic responses in allergic sheep. Pulmonary resistance (RL) was measured for 8 h after antigen challenge. Measurements of airway responsiveness to methacholine and bronchoalveolar lavage fluid (BALF) were obtained 8 h after challenge. Antigen challenge caused early and late increases in RL, airway hyperresponsiveness (AHR), and recruitment of neutrophils and eosinophils along with increases in TXB2 and LTB4 in BALF. ONO-5046 treatment significantly reduced both early and late bronchoconstriction, neutrophil recruitment, increases in LTB4 in BALF, and AHR. ONO-5046 post-treatment significantly reduced the increase in RL 8 h after antigen challenge. Another neutrophil elastase inhibitor, FR 134043, significantly reduced both early and late bronchoconstriction. ONO-5046 had little effect on calcium ionophore-induced LTB4 release from isolated neutrophils and whole blood obtained from drug-treated sheep. These findings suggest that neutrophil elastase is involved in antigen-induced bronchoconstriction and AHR mediated by neutrophil accumulation and 5-lipoxygenase products in allergic sheep.

Hypoxia-induced ANP secretion in subjects susceptible to high-altitude pulmonary edema

We investigated the effects of acute hypoxia (10% O2) on plasma level of atrial natriuretic peptide (ANP) and pulmonary hemodynamics in five subjects with a history of high-altitude pulmonary edema (HAPE). Plasma renin activity and plasma levels of aldosterone, epinephrine and norepinephrine were also measured. The plasma ANP levels in HAPE-susceptible subjects rose significantly in response to 10% O2 (from 34.8 +/- 5.4 to 51.4 +/- 7.3 pg.ml-1; P less than 0.05), not associated with any increase in either atrial pressure. Compared with six control subjects, the rise of ANP level was greater in HAPE-susceptible subjects (16.6 +/- 4.4 vs 3.9 +/- 1.2 pg.ml-1; P less than 0.05). There was a significant positive correlation between the rise of ANP level and the increase of pulmonary arterial pressure. No significant difference was observed in any of other hormonal responses to acute hypoxia between the two groups. We interpret these results as indicating that the ANP secretory response to acute hypoxia in HAPE-susceptible subjects, which is not mediated by an increase in atrial pressure, may be greater than that in nonsusceptible subjects in association with a greater pressor response of pulmonary circulation.

Nocturnal periodic breathing and arterial oxygen desaturation in acute mountain sickness

The objective of this case-control study was to investigate the relationship between periodic breathing (PB) and acute mountain sickness (AMS). Nine volunteers, healthy lowlanders between the age of 20 and 36 years stayed at a simulated altitude of 3700 m (485 Torr) for 24 h in a hypobaric chamber. A sleep study was carried out for more than 6 h. Arterial oxygen saturation (SaO 2 ) was monitored by finger oximetry on all subjects. PB was determined by a polysomnography (EEG, EOG, thoracic movement) in six subjects and was indirectly measured by studying the cyclic change of SaO 2 in three other subjects. The severity of AMS was assessed with the Environmental Symptoms Questionnaire. All subjects showed lower SaO 2 during sleep than when awake (65.0±6.4% versus 72.6±6.4%, p

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50=2.2 × 10−5 M) and angiotensin-II-induced pulmonary vasoconstriction (IC50=5.0 × 10−5 M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxiaor angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.

Pulmonary Function Tests of Mycobacterium avium-intracellulare Infection: Correlation with Bronchoalveolar Lavage Fluid Findings

Background: The pulmonary Mycobacterium avium-intracellulare (MAI) infection in patients with neither predisposing lung disease nor immunodeficiency is recognized to occur predominantly in older or middle-aged and thin females, and has characteristic chest computed tomography (CT) findings with multiple nodules and bronchiectasis. Objective: To investigate the pathophysiology with and individual of MAI infection with neither predisposing lung disease nor immunodeficiency. The bronchoalveolar lavage (BAL) fluid (BALF) was recovered directly from the affected segments identified by the chest CT. Methods: We performed a pulmonary function test (PFT) and BAL in 15 patients (all females) with MAI infection and 5 normal female volunteers. Results: The residual volume and the slope of phase III (ΔN2) were significantly increased and v̇25 was significantly decreased in the 15 patients compared with the normal control subjects. The patients’ BALF showed significant increases in neutrophils and activated CD4 lymphocytes, proinflammatory cytokines, and neutrophil elastase (NE) compared to those in the controls. We analyzed the PFT and BALF findings, and observed a significant correlation between the ΔN2 and interleukin (IL)-8 concentration (r = 0.65, p < 0.01), IL-8/albumin ratio (r = 0.51, p < 0.05) and NE/albumin ratio (r = 0.57, p < 0.05) in the BALF and ΔN2, respectively. Conclusions: These findings suggest that small airway dysfunction in MAI infection without predisposing lung disease is related to the inflammation probably related to the neutrophil.

Abnormal Breathing Pattern and Oxygen Desaturation during Sleep at High Altitude

It is well known that healthy low-altitude residents often develop abnormal breathing pattern and oxygen desaturation during sleep at high altitude, although few studies of sleep during long-term sojourn at high altitude have been conducted. The purpose of this study was to investigate changes in breathing pattan and oxygen desaturation during sleep at high altitude, and their relation to pattern of ascent and descent, as well as to the acclimatization process in low-altitude residents.