Kenji Miyamoto

Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema

Background: It has previously been shown that smokers with computed tomographic (CT) evidence of subclinical emphysema have signs of neutrophil activation, despite having no appreciable increase in the number of neutrophils in their bronchoalveolar lavage (BAL) fluid. Methods: The levels of the following chemoattractants in BAL fluid from 61 community based older volunteers classified into four groups according to current smoking status and the presence or absence of emphysema were determined: interleukin 8 (IL-8), epithelial neutrophil activating protein 78 (ENA-78) and leukotriene B4 (LTB4) which are primarily chemotactic for neutrophils; monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) which are predominantly chemotactic for mononuclear leucocytes. Results: Of the five chemoattractants studied, only the level of IL-8 in BAL fluid clearly distinguished between subjects with and without emphysema among current smokers (median values 34.7 and 12.2 pg/ml, respectively, p<0.01). In addition, the levels of IL-8 and neutrophil elastase-α1 protease inhibitor complex in BAL fluid were significantly correlated (r=0.65, p<0.01). There was no difference in either the release of IL-8 from cultured alveolar macrophages at 24 hours or the expression of IL-8 messenger RNA of alveolar macrophages in the two groups of current smokers with and without emphysema. Conclusion: An accelerated response of IL-8 to chronic smoking is a factor that characterises those smokers who are susceptible to pulmonary emphysema, although the cellular source of IL-8 remains to be determined.

Relation of Oxygen Delivery, Mixed Venous Oxygenation, and Pulmonary Hemodynamics to Prognosis in Chronic Obstructive Pulmonary Disease

We studied the relation of oxygen delivery, mixed venous oxygenation, and pulmonary hemodynamics to prognosis in 50 randomly selected patients with chronic obstructive pulmonary disease. Cardiac catheterization was performed when the patients were clinically stable. Four years later, 27 patients (54 per cent) had died of respiratory failure. At the time of catheterization, patients who subsequently lived were similar to those who died in age, physical characteristics, and hematocrit. Nonsurvivors had significantly lower arterial and mixed venous oxygen tension and significantly higher arterial and mixed venous carbon dioxide tension. The mean pulmonary arterial pressure, pulmonary arteriolar resistance, right ventricular work, coefficient of oxygen delivery, and cardiac index did not differ between the two groups. After inhalation of 100 per cent oxygen for one hour, the mixed venous oxygen tension of nonsurvivors rose to a level equivalent to that of survivors, and their mean pulmonary arterial pressure fell significantly. These results indicate that, with respect to oxygen supply to the tissues, mixed venous oxygenation is one of the important prognostic factors in chronic obstructive pulmonary disease. Pulmonary and right ventricular hemodynamics measured during periods of clinical stability do not differentiate nonsurvivors from survivors.

Cysteine proteinases and cystatin C in bronchoalveolar lavage fluid from subjects with subclinical emphysema

This study examined the role of cysteine proteinases and their inhibitor in the development of emphysema in comparison with neutrophil elastase (NE) complexed with alpha1-protease inhibitor (NE-alpha1-PI), which was previously demonstrated to be increased in bronchoalveolar lavage (BAL) fluid from subjects with subclinical emphysema. Eight nonsmokers and 31 current smokers with (n=17) and without (n=14) emphysema, as evidenced by lung computed tomographic scans, were studied. The concentrations of immunologically detected cathepsin L and cystatin C, but not cathepsin B, were significantly increased in BAL fluid from the smokers with emphysema compared with those without emphysema, although the activity of cathepsin L, measured using a synthetic substrate and cathepsin L, released from cultured alveolar macrophages at 24 h, did not show any significant difference between the two groups. When comparison was made only for the subjects aged <60 yrs, the difference between the two groups disappeared for cathepsin L, but remained for NE-alpha1-PI. There was no significant correlation between the level of cathepsin L and that of NE-alpha1-PI in BAL fluid from the subjects with emphysema. In conclusion, increased levels of cathepsin L and cystatin C were demonstrated in bronchoalveolar lavage fluid from subjects with subclinical emphysema. However, the roles of cathepsin L and neutrophil elastase in the development of emphysema may vary between subjects and between the young and the old.

Ventilatory and heart rate responses to hypoxia and hypercapnia in patients with diabetes mellitus.

The ventilatory response to isocapnic progressive hypoxia and hyperoxic progressive hypercapnia in 24 diabetic patients were compared with those of sex and age matched normal control subjects. The heart rate response to hypoxia was also measured in both groups. In diabetic patients the ventilatory and heart rate responses to hypoxia were significantly lower than those in the control group (0.10 v 0.24 l/min/% fall/m2 and 0.5 l v 1.27 beats/min/% fall respectively). The ventilatory response to hypercapnia was significantly higher (1.09 v 0.76 l/min/mm Hg/m2) in the diabetic patients. There was a significant correlation between the hypoxic ventilatory response and the heart rate response in diabetic patients (r = 0.56), but not in the control group (r = 0.28). In addition, both the ventilatory and the heart rate responses to hypoxia in diabetic patients had weak but significant correlations with the heart rate variation during deep breathing. It is concluded that the ventilatory and heart rate responses to hypoxia in diabetic patients are impaired, whereas the ventilatory response to hypercapnia is well preserved.

Exhaled Nitric Oxide – Is It Really a Good Marker of Airway Inflammation in Bronchial Asthma?

Background: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. Objective: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. Methods: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. Results: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 ± 0.7 ppb) or bronchiectasis (5.4 ± 1.3 ppb) was not significantly increased compared with the controls (6.0 ± 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 ± 2.0 ppb). Conclusions: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.

Purification and characterization of glutathione disulfide-stimulated Mg2+-ATPase from human erythrocytes

We have previously shown the presence of two different forms of glutathione disulfide (GSSG)-stimulated Mg2+-ATPases in human erythrocytes. We have now investigated a low-Km form of the enzyme from human erythrocytes. Purification of the enzyme was performed to apparent homogeneity involving procedures of affinity chromatography and gel filtration. The enzyme was composed of two non-identical subunits of Mr = 82K and 62K. The enzyme reconstituted into phospholipid vesicles showed both GSSG-stimulated Mg2+-ATPase activity (285 nmol Pi released/mg protein/min) and active GSSG transport activity (320 nmol GSSG/mg protein/min). The amino acid composition of the enzyme was similar to that of the enzyme purified from cytoplasmic membranes of human hepatocytes. These enzymes were immunologically cross reactive. These results indicate that this enzyme functions in the active transport of GSSG as it possibly does in hepatocytes.

Effects of IL-1beta, TNF-alpha, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells.

Objective:  Cytokines have been implicated in the pathophysiology of pulmonary hypertension. We sought to explore the possibility that prostacyclin is a link.

Decline in FEV1 in Community-Based Older Volunteers with Higher Levels of Neutrophil Elastase in Bronchoalveolar Lavage Fluid

Background: Neutrophil elastase (NE) is thought to be one of the key proteinases in the development of chronic obstructive pulmonary disease (COPD). Previously, we have shown that the NE-α1-proteinase inhibitor (NE-α1PI) complex in bronchoalveolar lavage (BAL) fluid was markedly elevated in asymptomatic smokers who had subclinical emphysema on CT scans. We proposed that excessive NE-α1PI complex in BAL fluid was a factor which might differentiate smokers who were developing emphysema from others. Objective: In this study, we addressed the question of whether elevated levels of the NE-α1PI complex in BAL fluid are linked to the accelerated decline in pulmonary functions in those subjects. Methods: We conducted a follow-up study to analyze the decline in FEV1 for 4.3 years on average for 26 community-based volunteers who had received pulmonary function tests, CT scans and BAL. The levels of the NE-α1PI complex in BAL fluid and in plasma was measured. Results: Neither pulmonary function measurements nor the presence of emphysema on CT scans could predict the decline in FEV1. The number of inflammatory cells in BAL fluid was also not an indicator of progression. By contrast, subjects with higher levels of the NE-α1PI complex in BAL fluid had a significantly accelerated decline in FEV1 compared to those with lower levels. Conclusion: These data seem to support the hypothesis that NE in the lung is related to the onset and/or progression of COPD.

PACS experience at the University of Hokkaido Medical School

Seven months experiences of a filmless PACS (named HU-PACS) which covers Radiology, Orthopedic, Internal medicine and General Surgery departments are reported. The PACS has only 20 Image terminals but handles more than 50% of images produced which is about 1000 images per working day. Physicians of the departments have many criticisms and opinions on the PACS but generally speaking it is well accepted and inspiring the physicians to improve the PACS in its image quality and other functions instead of being discarded. Preliminary clinical assessment are performed and reported also.

Pulmonary function is diminished in older asymptomatic smokers and ex-smokers with low attenuation areas on high-resolution computed tomography

OBJECTIVES The relation between pulmonary function and low attenuation areas (LAAs) on high-resolution computed tomography (HRCT) is not clear in subclinical pulmonary emphysema. Accordingly we examined pulmonary function and HRCT in asymptomatic community-based volunteers. DESIGN The existence of LAAs on CT was evaluated independently by three respiratory physicians who were blind to the pulmonary function test data and smoking histories of the subjects. The LAA grade was assessed by a visual scoring method from 0 to 5, and the individual LAA score and the values of pulmonary function tests were compared. PARTICIPANTS 57 subjects aged from 32 to 82 years [mean 62 +/- (SD) 11] years were enrolled in the study. RESULTS LAAs were found in 20 of the 49 subjects who were current or ex-smokers but in none of the 8 who never smoked. LAAs observed were mostly less than 25% of the total areas of the lungs. Although all mean values were within normal limits, the forced expiratory volume in 1 s (%pred), maximal expiratory flow at 50% of forced vital capacity (%pred), diffusing capacity of the lungs for carbon monoxide (DLCO; %pred) and diffusing capacity for carbon monoxide per unit alveolar volume (DLCO/VA; %pred) were all significantly less in those with LAAs than in those without LAAs. There was also a significant tendency for DLCO %pred and DLCO/VA %pred to decrease as the LAA scores increased. CONCLUSION Those who have LAAs on CT have a small but significant deterioration in pulmonary function tests even if the LAAs observed are minimal or mild in degree. Longitudinal studies will be necessary to determine whether LAAs on CT identify the subjects who will develop airflow obstruction over time.