[Physiological function of the lung; fundamentals on inspiratory capacity].

Inspiratory capacity (IC) is recently highlighted in the clinical field of chronic obstructive pulmonary disease (COPD). Generally, IC is positively associated with exercise capacity and survival prognosis. Since chest surgery generally results in restive change in vital capacity, the decrease in IC potentially causes dysfunction of exercise capacity and dyspnea on exertion, which frequently results in disuse syndrome and deterioration in the quality of life. Although IC seems to be less appreciated, it has more important clinical implementation in terms of exercise capacity and dyspnea than one second forced expiratory volume (FEV1.0). In this aspect, surgical strategies to prevent unnecessary decrease in IC should be cared. Also, appropriate treatments such as chest physiotherapy or exercise training are needed to increase IC for the post-operative patients.

Hypoxia induces transcription factor ETS-1 via the activity of hypoxia-inducible factor-1.

ETS-1 plays an important role in angiogenesis and cancer invasion, and hypoxia is a common feature in these phenomena. We examined whether hypoxia influenced ETS-1 expression. Hypoxia induced ETS-1 in a human bladder cancer cell line, T24, and promoter analysis revealed that the deletion of -424 to -279 bp from the human ETS-1 promoter decreased the hypoxia-mediated inducibility. This region contained a hypoxia responsive element-like sequence, and HIF-1 bound to it under the hypoxic condition. Double-stranded synthetic oligonucleotides of this sequence as a decoy inhibited the hypoxia-mediated inducibility. These results indicate that hypoxia induces ETS-1 via the activity of HIF-1.

Role of GABA within the nucleus tractus solitarii in the hypoxic ventilatory decline of awake rats.

The purpose of this study was to examine our hypothesis that gamma-aminobutyric acid (GABA) in the nucleus tractus solitarii (NTS) may be related to the hypoxic ventilatory decline (HVD) and that chemoreceptor stimulation was essential to activate this mechanism. We used unanesthetized, freely moving rats in this study. An in vivo microdialysis technique was used to measure the extracellular GABA concentration ([GABA]o), and an in vivo microinjection technique was used to examine the effects of the GABA agonists and antagonists on the ventilation during hypoxia. The GABA agonists injected into the NTS attenuated the ventilation during hypoxia. By hypoxic exposure, [GABA]o was increased during the HVD. However, by carotid body denervation (CBD), this GABA increase was abolished. Although GABA antagonists microinjected into the NTS during the HVD phase significantly increased the depressed ventilation, this effect on the ventilation was abolished by CBD. These results suggest that the GABA in the NTS has a pivotal role in the HVD and that this mechanism is not activated without chemoreceptor stimulation.

Thoracoscopic lung volume reduction surgery for pulmonary emphysema patients with severe hypercapnia.

OBJECTIVES: We assessed whether hypercapnia patients with an extremely high level of PaCO2 > or = 60 mmHg were suitable candidates for lung volume reduction in the treatment of severe pulmonary emphysema. METHODS: Of 65 patients undergoing lung volume reduction surgery between May 1993 and August 1997, 6 (9.23%) who had a preoperative rest room air blood gas level of PaCO2 > or = 60 mmHg were selected for study. All patients underwent video-assisted thoracoscopic surgery. Of the 6 with severe hypercapnia, 5 underwent the unilateral procedure and 1 the bilateral procedure. RESULTS: All severe hypercapnia patients showed significant clinical improvement. When assessed at 3 to 6 months after lung volume reduction surgery, significant improvements were seen in mean forced expiratory volume in 1 second (preop: 0.44 +/- 0.04 L; postop: 0.74 +/- 0.20 L; p < 0.01), for a magnitude improvement of 69.8%, and in trapped gas volume (preop: 3.28 +/- 1.11 L; postop: 1.61 +/- 1.02 L; p < 0.05). Arterial blood gas analysis showed significant improvement in PaO2 from 51.1 +/- 6.68 mmHg to 69.8 +/- 7.87 mmHg (p < 0.001) with a decrease in PaCO2 from 70.4 +/- 9.41 mmHg to 46.9 +/- 3.44 mmHg (p < 0.01). Postoperative follow-up averaged 55 months (43-69 months). All but 1 patient remain alive and well. CONCLUSION: Patients with severe pulmonary emphysema accompanied by hypercapnia can gain relief and a better quality of life through volume reduction surgery and should not be excluded from surgical treatment simply based on this condition. Selection should involve a comprehensive view of the patient's condition that includes criteria such as the results of radiographic diagnosis and detailed pulmonary function tests.

Quantitative assessment of the pharyngeal airway by dynamic magnetic resonance imaging in obstructive sleep apnea syndrome.

Dynamic changes in the pharyngeal airway of patients with obstructive sleep apnea syndrome (OSAS) were evaluated by quantitating the findings of real-time imaging performed during wakefulness and spontaneous sleep by means of dynamic magnetic resonance imaging (MRI). Six patients with OSAS and 3 non-OSAS subjects, selected prospectively and randomly, underwent polysomnography and dynamic MRI. The cross-sectional areas of the soft palate and oropharynx and the anterior-posterior airway dimensions seen during wakefulness and spontaneous sleep were calculated by US National Institutes of Health imaging software. On the basis of a case control study, comparisons were made with age-matched and body mass index-matched obese non-OSAS snorers. Spontaneous sleep caused significant obstruction and narrowing of various sites of the pharyngeal airway in the OSAS patients, but not in the non-OSAS subjects. During wakefulness, the non-OSAS subjects showed no marked narrowing of the pharyngeal airways, whereas a transient but significant narrowing was observed in the OSAS patients. The mean values of both the cross-sectional area and the anterior-posterior diameter at the soft palate were significantly reduced by spontaneous sleep in the OSAS patients. Dynamic MRI in awake OSAS patients shows promise as a routine diagnostic tool for localizing the upper airway collapse for appropriate selection of surgical therapy.

Differential expression of adrenomedullin and its receptor component, receptor activity modifying protein (RAMP) 2 during hypoxia in cultured human neuroblastoma cells.

Adrenomedullin is a potent vasodilator peptide originally isolated from a pheochromocytoma. Recently, a novel adrenomedullin receptor has been identified as a complex consisting of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 2. To explore possible pathophysiological roles of adrenomedullin and its receptor component RAMP2 in hypoxic tissues, we studied effects of hypoxia on expression of adrenomedullin and RAMP2 in two human neuroblastoma cell lines, IMR-32 and NB69, by radioimmunoassay and Northern blot analysis. Expression levels of adrenomedullin were increased by hypoxia in both cell lines. Treatment with cobalt chloride or desferrioxamine mesylate also increased expression levels of adrenomedullin mRNA. On the other hand, expression levels of RAMP2 mRNA were decreased in IMR-32 cells and were not changed in NB69 cells by hypoxia. Treatment with cobalt chloride or desferrioxamine mesylate decreased expression levels of RAMP2 mRNA in both IMR-32 and NB69 cells. These findings indicate that adrenomedullin expression is induced during hypoxia in IMR-32 and NB69 neuroblastoma cells, but RAMP2 expression is rather suppressed under the same conditions. The decreased expression of RAMP2 and the ADM expression induction under hypoxia may constitute one mechanism of cellular adaptation to hypoxic stress.

Inspiratory effort sensation to added resistive loading in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Repeated episodes of upper-airway occlusion are the main characteristics of patients with obstructive sleep apnea (OSA) during sleep. It has been reported that an impairment in the sensation of detection and a depression of ventilatory compensation to added load could be observed in such patients. In this study, we examined patients with OSA to evaluate the inspiratory effort sensation (IES), ventilation, and mouth occlusion pressures during added resistive loading while awake and to determine whether they can be reversed by nasal continuous positive airway pressure (CPAP) treatment. DESIGN: A hospital-based case-control study. SETTING: A sleep laboratory of a medical unit in Japan. SUBJECTS: Seventeen patients with moderate to severe OSA and 10 control subjects were included in this study. MEASUREMENTS: All patients with OSA had undergone standard nocturnal polysomnography. Patients with OSA and control subjects were evaluated for IES measured by a modified Borg score, ventilation, and mouth occlusion pressure during control and inspiratory resistive loaded breathing. These tests were repeated in all patients with OSA after 2 weeks of nasal CPAP treatment. RESULTS: IES to inspiratory resistive loading was lower in patients with OSA than in control subjects. There were no differences in ventilation and mouth occlusion pressure between patients and control subjects during loaded breathing. After 2 weeks of nasal CPAP, the decreased IES was increased in patients with OSA. CONCLUSION: In patients with OSA, the decreased IES to inspiratory resistive loaded breathing is reversible with nasal CPAP. This could be one additional benefit of nasal CPAP in the treatment of OSA.

Induction of adrenomedullin during hypoxia in cultured human glioblastoma cells.

Adrenomedullin is a potent vasodilator peptide originally isolated from pheochromocytoma. Adrenomedullin is produced by various types of cells including neurons and astrocytes. To explore possible pathophysiological roles of adrenomedullin in hypoxic brain, we studied the effects of hypoxia on the expression of adrenomedullin in T98G human glioblastoma cells by radioimmunoassay and northern blot analysis. Expression levels of adrenomedullin mRNA and immunoreactive adrenomedullin levels in the culture medium were increased by hypoxia about six- and about threefold, respectively. Treatment with cobalt chloride increased expression levels of adrenomedullin mRNA about threefold and immunoreactive adrenomedullin levels in the culture medium about threefold in T98G cells. Using actinomycin D, we showed that hypoxia did not cause the stabilization of the adrenomedullin mRNA, suggesting that the increased adrenomedullin mRNA levels in response to hypoxia are caused mainly by increased transcription. Treatment with cycloheximide caused increases in adrenomedullin mRNA levels in both normoxic and hypoxic states, raising the possibility that some protein(s) may act as a suppressor of adrenomedullin gene expression in T98G cells. These findings indicate that adrenomedullin is highly induced during hypoxia in T98G glioblastoma cells and suggest that increased expression of adrenomedullin during hypoxia may be important in the defense against hypoxia or ischemia in the brain.

[Obesity and obesity hypoventilation syndrome].

Some patients with obesity show chronic hypercapnia while awake. Such patients are referred to as obesity hypoventilation syndrome(OHS). Particularly, patients with profound obesity who have clinical features of sleep disordered breathing, hypersomnolence, cor pulmonale and so on represent the Pickwickian syndrome. The mechanisms of hypoventilation in OHS are multifactorial. The level of the blunted chemosensitivity, mechanical impairments of the respiratory system, the severity of the sleep-disordered breathing, and chronic hypoxemia may be important determinants of chronic hypoventilation. In this paper, the characteristics of pulmonary functions in obesity and the possible mechanisms of hypoventilation in patients with OHS were reviewed. Furthermore, the definition of OHS and descriptions of thr severity of OHS as recommended by Respiratory Failure Research Committee of Japanese Ministry of Health and Welfare are introduced.

Expression of Glut-4 and Glut-1 transporters in rat diaphragm muscle.

Glucose transporters (Gluts) are a family of membrane proteins responsible for the transport of glucose across cellular membranes. Generally, alterations of Gluts expression in limb skeletal muscle have been reported. However, the changes of Glut isoforms in respiratory muscle which contracts with a duty cycle have rarely been studied. This study was performed to evaluate at the light microscopy level the expression of Glut-4 and Glut-1 transporters in normal and denervated diaphragm by immunohistochemistry method with specific Gluts antibodies. The results showed Glut-4 immunoreactivity in both the cell periphery and the interior of myocytes. Glut-1 was also present in the cell border and in the interior of myocytes in control diaphragm. However, Glut-4 staining was stronger than Glut-1 staining in control diaphragm. In denervated hemidiaphragm, the Glut-4 immunolabelling decreased and Glut-1 increased. These data indicated that (1) Glut-4 and Glut-1 transporters were observed in diaphragm; and (2) there were alterations in the expression of both glucose transporters after denervation. These alterations in Glut isoforms after denervation may be associated with the removal of innervation itself, and/or may partly result from passive stretch imposed by inspiratory activation of the contralateral side.

Effects of nasal continuous positive airway pressure on awake ventilatory responses to hypoxia and hypercapnia in patients with obstructive sleep apnea.

This study was aimed to examine the short- and long-term effects of nasal continuous positive airway pressure (CPAP) on the chemosensitivity to hypoxia and hypercapnia in the patients with obstructive sleep apnea (OSA). Awake ventilatory responses to hypoxia and hypercapnia were examined in 28 patients (3 female) with moderate to severe OSA. All these tests were examined before and after 2 weeks of nasal CPAP. In 10 patients these tests were repeated after 3-6 months of nasal CPAP. All were also tested for spirometry and arterial blood gas analysis. Patients were middle-aged (48.9 +/- 9.9 years) and their mean apnea-hypopnea index was 58.3 +/- 20.4/hour. After 2 week of nasal CPAP, PaO2 significantly increased (77.7 +/- 11.8 vs. 84.6 +/- 9.8 mmHg) and PaCO2 significantly decreased (44.9 +/- 3.8 vs. 42.3 +/- 3.7 mmHg). The ventilatory response to hypoxia significantly decreased (0.80 +/- 0.51 vs. 0.61 +/- 0.51 liter/min/%) whereas the ventilatory response to hypercapnia significantly increased after 2 weeks (1.47 +/- 0.73 vs. 1.80 +/- 0.76 liter/min/mmHg). Similar findings were also observed after 3-6 months of nasal CPAP in 10 OSA patients. Nasal CPAP treatment can alter the ventilatory responses in patients with OSA.

Role of ventilatory drive in asthma and chronic obstructive pulmonary disease.

The ventilatory drive is affected by several factors such as chemosensitivity, basal arterial oxygen or carbon dioxide tension, mechanical impedance, and respiratory muscle dysfunction. Blunted ventilatory drive or a decrease in the perception of dyspnea in bronchial asthma and chronic obstructive pulmonary disease (COPD) could lead to a decrease in the alarm reaction to dangerous situations such as severe airway obstruction, severe hypoxemia, or severe hypercapnia. This could delay management and treatment, causing an increase in the morbidity and mortality of patients with bronchial asthma and COPD. The ventilatory drive to chemical stimuli can be altered by a beta-2-agonist, oxygen administration; and lung volume reduction, and an increased dyspnea sensation may be improved by corticosteroid, chest wall vibration, or lung volume reduction. The ventilatory drive has been found to play a key role in determining the severity of asthma and COPD.

Correlation of unilateral thoracoscopic lung volume reduction with improvement in lung function and exercise performance in patients with severe pulmonary emphysema.

This study was conducted to investigate the correlation of thoracoscopic lung volume reduction to changes in pulmonary function and exercise performance in patients with pulmonary emphysema. Unilateral thoracoscopic lung volume reduction treatment was performed in 30 patients with severe pulmonary emphysema. If large bullae were present, they were excised using an endoscopic stapling device, and the emphysematous pleura was contracted by neodymium:yttrium-aluminium-garnet laser to reduce the volume of nonfunctional lung air space. Pulmonary function and incremental exercise tests were performed before and at least 3 months after treatment. Follow-up functional evaluation showed a highly significant improvement in the forced expiratory volume in 1s (FEV1), forced vital capacity, static compliance, and maximal oxygen uptake. The functional residual capacity as measured by the gas dilution method (FRCgas), was unchanged; however, it was found to be decreased significantly when measured by body plethysmograph (FRCbox). Positive correlations existed between the reduction in FRCbox and the increase in FEV1 (r = 0.586, P = 0.0042) and maximal oxygen uptake (r = 0.550, P = 0.018). Pulmonary ventilation and exercise ability in patients with pulmonary emphysema were improved in a volume-dependent manner by thoracoscopic lung volume reduction. These findings indicate that patients with a preoperative trapped gas volume level exceeding 11 would be ideal candidates for thoracoscopic lung volume reduction.

Volume-pressure properties of the upper airway in normal subjects and patients with obstructive sleep apnoea.

The aim of this study was to examine the volume-pressure (V-P) characteristics of isolated upper airways in normal subjects and patients with obstructive sleep apnoea (OSA) and to ascertain whether an increase in upper airway muscle activity affects these characteristics. We studied upper airway pressure changes during volume changes by inflation and deflation of air volumes of 5, 10, 15 and 20 mL without and with submental electrical stimulation, during voluntary closing of the glottis, in seven normal subjects and 13 OSA patients. Volume-pressure properties of the upper airway were assessed by elastance (Euaw) which was obtained from the slope of the regression line of the V-P relationships. Euaw in OSA patients was 0.52 +/- 0.08 cmH2O/mL, which was greater than in normal subjects (0.26 +/- 0.06 cmH2O/mL). Submental stimulation increased Euaw in both OSA patients and normal subjects (0.70 +/- 0.11 cmH2O/mL and 0.41 +/- 0.11 cmH2O/mL, respectively). These results suggest that upper airways of OSA patients during wakefulness are less collapsible than those of normal subjects, and that, in both groups, submental stimulation may stiffen the upper airway.

Nocturnal blood pressure during apnoeic and ventilatory periods in patients with obstructive sleep apnoea.

The exact nature of asleep blood pressure in relation to awake blood pressure is still unclear in patients with obstructive sleep apnoea. This study aimed: 1) to investigate the asleep blood pressure in both apnoeic and ventilatory periods; 2) to determine the diurnal and nocturnal factors correlated with the changes in blood pressure from apnoea to ventilatory periods during sleep. Thirty-two patients, newly diagnosed as moderate to severe obstructive sleep apnoea with a standard nocturnal polysomnography, were enrolled. The blood pressure was monitored by using the noninvasive continuous monitoring method during polysomnographic study. The mean blood pressures in ventilatory periods during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were 117.5+/-17.9 mm Hg and 128.8+/-21.9 mm Hg, and those in apnoea periods were 94.5+/-15.4 mm Hg and 102.7+/-19.0 mm Hg. The average blood pressure during NREM sleep (103.0+/-16.1 mm Hg) was higher than the awake blood pressure (97.0+/-15.7 mm Hg). The blood pressure during REM sleep was greater than that during NREM sleep. The changes in the nocturnal blood pressure from apnoea to ventilatory periods were inversely correlated with the age and nocturnal mean nadir saturation. In conclusion, patients with obstructive sleep apnoea have higher asleep blood pressure than awake blood pressure.

Influence of sustained hypoxia on the sensation of dyspnea.

We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

Pulmonary function and regional distribution of emphysema as determined by high-resolution computed tomography.

In patients with pulmonary emphysema, emphysematous changes are not uniform and vary from minimum alveolar destruction to advanced bullous formation, depending on the lobe or site in the lungs. However, we have little knowledge on whether or how this nonuniformity or localization affects pulmonary function in PE patients. Therefore, we measured the computed tomography (CT) density of divided sites in lungs with high-resolution CT images from 25 PE patients (FEV1.0%, mean +/- SD 36 +/- 9%, %DLCO 48 +/- 16%, all men, 68 +/- 4 years) and compared them to various parameters of pulmonary function. The mean CT density of whole lungs correlated with 12 pulmonary function parameters including FEV1.0 and diffusion capacity. When both lung fields were divided into peripheral, intermediate and central portions, the CT density of the central portion correlated with all pulmonary function parameters with which CT density of whole lungs correlated. In contrast, the CT density of the peripheral portion significantly correlated with only 7 parameters with smaller correlation coefficient values than those of the central portion. When divided into upper, middle and lower portions, the CT densities of upper, middle and lower portions correlated with 6, 8 and 10 of the 12 pulmonary function parameters which correlated with the density of whole lungs, respectively. The delta value of CT densities between the upper and lower portions or between the lateral and medial portions correlated with obstructive impairment (FEV1.0 and FEV1.0%). These findings suggest that (1) central rather than peripheral emphysematous changes affect pulmonary function, and (2) uniformity of emphysematous change correlates with the severity of airway obstruction in PE patients.

New strategies of screening and treatment for sleep apnea syndrome.

The prevalence of sleep apnea syndrome (SAS) is approximately 7.5% in Japanese adults aged 18-68 years old. SAS is characterized by repeated episodes of apnea, especially obstructive apnea, during sleep. Severe SAS has life-threatening complications such as pulmonary hypertension, arrhythmias, right heart failure or brain damage, which could be caused by hypoxemia and/or hypercapnia. Upper airway relaxation is responsible for the obstruction during apnea, and an increase in the activities of the upper airway muscles dilates and stiffens the upper airway wall. Maintaining the activities of the upper airway muscles may contribute to keeping the airway patent. Submental electrical stimulation of the upper airway muscles would be a novel treatment method for obstructive apnea.