Biomedical subjects
Mutsuo Yamaya
Publications and source records attributed to Mutsuo Yamaya.
Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease.
RATIONALE: Exhaled carbon monoxide (CO) and arterial blood carboxyhemoglobin concentrations (Hb-CO) increase in inflammatory pulmonary diseases. OBJECTIVES: To study whether arterial Hb-CO is useful to monitor disease activity in patients with chronic obstructive pulmonary disease (COPD) who had stopped smoking. METHODS: We measured arterial Hb-CO, arteriovenous Hb-CO differences, and FEV1 in 58 patients with COPD and 61 ex-smoking control subjects. RESULTS: Arterial Hb-CO concentrations in patients at stable conditions were higher than those in control subjects (p < 0.0001). Furthermore, the Hb-CO concentrations in patients at the exacerbations (p < 0.0001) were higher than those at the stable conditions. Arterial Hb-CO concentrations in patients at stage III were higher than those in patients at stage II, and the Hb-CO concentrations in patients at stage IV were higher than those in patients at stage III at the stable conditions and exacerbations. Arterial Hb-CO correlated with exhaled CO in patients with COPD at stage II and stage III at the exacerbations. Arterial Hb-CO inversely correlated with the arterial blood partial oxygen pressure and FEV1. Arteriovenous Hb-CO differences in patients at the exacerbations did not differ from those in patients at stable conditions and from those in control subjects. Moreover, arterial Hb-CO correlated with serum C-reactive protein values and serum lipid peroxide concentrations. CONCLUSIONS: These findings suggest that increased arterial Hb-CO may relate to severity in patients with COPD because of lung and systemic inflammation and production of reactive oxygen species.
The proton pump inhibitor lansoprazole inhibits rhinovirus infection in cultured human tracheal epithelial cells.
To examine the effects of lansoprazole, a proton pump inhibitor, on rhinovirus infection in airways, human tracheal epithelial cells were infected with a major subgroup of rhinoviruses, type 14 rhinovirus. Rhinovirus increased the mRNA expression of intercellular adhesion molecule-1 (ICAM-1) in the cells, the major rhinovirus receptor, and the content of the soluble form of ICAM-1 (sICAM-1) and cytokines in supernatants. Lansoprazole reduced supernatant titers and RNA of rhinovirus, the susceptibility to rhinovirus infection, the ICAM-1 mRNA production, the number and fluorescence intensity of acidic endosomes in the cells, and supernatants sICAM-1 and cytokine concentrations including interleukin-1beta. Antibody to interleukin-1beta reduced baseline and rhinovirus-induced ICAM-1 production. These results suggest that lansoprazole inhibits rhinovirus infection by reducing ICAM-1 via partly endogenous production of interleukin-1beta, and by blocking the rhinovirus RNA entry into the endosomes. Lansoprazole may modulate airway inflammation by reducing the production of cytokines and ICAM-1 in rhinovirus infection.
Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism.
Heme oxygenase-1 (HO-1) acts in cytoprotection against oxidants and aromatic hydrocarbons in cigarette smoke. A (GT)(n) dinucleotide repeat in the 5'-flanking region of the human HO-1 gene (alias HMOX1) reduces HO-1 inducibility and shows length polymorphism, which is grouped into three classes: class S (<27 GT), class M (27-32 GT), and class L (>/=33 GT) alleles. To investigate the correlation between the HO-1 gene polymorphism and the development of lung adenocarcinoma, we screened 151 Japanese patients with lung adenocarcinoma and 153 control subjects. Patients and control subjects were frequency-matched by age, gender, smoking history and proportion of chronic pulmonary emphysema. The proportion of class L allele frequencies, as well as that of genotypic frequencies in L allele carriers (LL, LM, and LS), were significantly higher in patients with lung adenocarcinoma than those of control subjects. The adjusted odds ratio (OR) for lung adenocarcinoma with class L allele vs non-L allele (M+S) was 1.6 [95% confidence interval (CI) 1.0-2.5, P=0.03] and that with L allele carriers vs. non-L allele carriers was 1.8 (95% CI 1.1-3.0, P=0.02). Furthermore, the risk of lung adenocaricinoma for L allele carriers versus non-L allele carriers was much increased in the group of male smokers (OR=3.3, 95% CI 1.5-7.4, P=0.004). However, in the female non-smokers, the proportion of L allele carriers did not differ between patients and control subjects (OR=0.93, 95% CI 0.4-2.0, P=0.85). These findings suggest that the large size of a (GT)(n) repeat in the HO-1 gene promoter may be associated with the development of lung adenocarcinoma in Japanese male smokers.
A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity.
Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg(-1) day(-1)), dalteparin (75 units kg(-1) day(-1)) or danaparoid (50 units kg(-1) day(-1)). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours.
Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells.
Macrolide antibiotics have clinical benefits in patients with diffuse panbronchiolitis and in patients with cystic fibrosis. Although many mechanisms have been proposed, the precise mechanisms are still uncertain. We examined the effects of erythromycin on bactericidal activity of airway surface liquid secreted by cultured human tracheal epithelial cells. Airway surface liquid was collected by washing the surface of human tracheal epithelial cells with a sodium solution (40 meq/l). Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa were incubated with airway surface liquid, and the number of surviving bacteria was examined. The number of bacteria in airway surface liquid from the cells cultured in medium alone was significantly lower than that in the sodium solution. Furthermore, the number of bacteria in airway surface liquid from the cells treated with erythromycin was significantly lower than that in airway surface liquid from the cells treated with solvent alone. The production of mRNA and protein of human beta-defensin-1 and human beta-defensin-2 was significantly increased by erythromycin. Bactericidal activity of airway surface liquid was observed at low concentrations (40 meq/l) of sodium but not at higher concentrations (> or =80 meq/l). Airway surface liquid did not contain significant amounts of antibiotics supplemented in the culture medium. Erythromycin at the levels in airway surface liquid and in culture medium did not inhibit bacterial growth. These results suggest that erythromycin may increase bactericidal activity of airway surface liquid in human airway epithelial cells through human beta-defensins production and reduce susceptibility of the airway to bacterial infection.
Interleukin-1beta gene polymorphisms associated with COPD.
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Anticoagulant therapy for idiopathic pulmonary fibrosis.
STUDY OBJECTIVE: To evaluate the effect of anticoagulant therapy on the survival of patients with idiopathic pulmonary fibrosis (IPF). DESIGN: Prospective study. SETTING: Five hospitals located in the Miyagi prefecture in Japan, including a university hospital, a Red Cross hospital, two public general hospitals, and a municipal hospital. PATIENTS: Fifty-six patients with IPF (mean age, 69.4 years; range, 47 to 89) admitted to the hospitals from April 2001 to April 2004. INTERVENTIONS: Patients were assigned to receive prednisolone alone or prednisolone plus anticoagulant therapy. The anticoagulants included oral warfarin in an outpatient setting and low-molecular-weight heparin for rehospitalized patients with severely progressive respiratory failure. MEASUREMENTS AND RESULTS: There was no difference in baseline characteristics, including age, gender, clinical condition, pulmonary function, and plasma d-dimer level between the non-anticoagulant group and the anticoagulant group. The overall survival and hospitalization-free periods were assessed. There was a significant difference between survival curves of the non-anticoagulant group and the anticoagulant group, with a 2.9 hazard ratio (p = 0.04, Cox regression model). There was no significant difference in the probability of a hospitalization-free period between groups. The major cause of clinical deterioration was acute exacerbation during follow-up in the present study. Therefore, the mortality and plasma d-dimer levels in patients with an acute exacerbation were also assessed. The mortality associated with acute exacerbations of IPF in the anticoagulant group was significantly reduced compared to that in the non-anticoagulant group (18% vs 71%, respectively; p = 0.008, Fisher Exact Test). Furthermore, the plasma d-dimer levels in patients who died were significantly higher than those in survivors during acute exacerbation of IPF (3.3 +/- 2.3 microg/mL vs 0.9 +/- 0.7 microg/mL, p < 0.0001). Histologic analysis performed in three patients who died due to an exacerbation of IPF in the non-anticoagulant group demonstrated the features of usual interstitial pneumonia and acute lung injury. CONCLUSIONS: Our data suggested that plasma d-dimer levels are associated with mortality in patients with an acute exacerbation of IPF, and that anticoagulant therapy has a beneficial effect on survival in patients with IPF.
Inflammatory and bronchospastic factors in asthma exacerbations caused by upper respiratory tract infections.
It is still uncertain how viral respiratory infections cause acute exacerbations of bronchial asthma, although several mechanisms have been proposed. We studied the relationship between the airway narrowing and the inflammatory and bronchospastic factors in peripheral venous blood and urine, in 30 patients with asthma at the exacerbations caused by upper respiratory tract infections (URTIs). Acute exacerbations caused decreases in peak expiratory flow rate (PEFR) in all 30 patients with asthma. Asthma exacerbations caused the rises in serum levels of interleukin-6, soluble intercellular adhesion molecule-1 and eosinophil cationic protein, concentrations of urinary leukotriene E4 and plasma histamine, compared with those in patients with asthma at a stable condition and those in 30 control subjects (p < 0.05). The values of PEFR at the exacerbations correlated with the levels of these factors. Treatment with oral glucocorticoids reversed the decreases in PEFR and the increases in these factors. At the onset of URTIs, rhinovirus and influenza type A virus were identified in 13 and 7 patients, respectively. Each of parainfluenza virus, adenovirus, and enterovirus was identified in one patient. These findings suggest that respiratory viral infections may cause acute asthma exacerbations via the production of mediators that induce inflammation and bronchospasm.
Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in Japan.
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Increased arterial carboxyhemoglobin concentrations in elderly patients with silicosis.
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Arterial carboxyhemoglobin concentrations in elderly patients with operable non-small cell lung cancer.
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Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases.
PURPOSE: Exhaled carbon monoxide and arterial blood carboxyhemoglobin concentrations increase in inflammatory pulmonary diseases. The present study was undertaken to elucidate whether arteriovenous carboxyhemoglobin (a-vHb-CO) concentration differences are also useful to define the site of inflammation, either in the lung or organs other than the lung. MATERIALS AND METHODS: We examined concentrations of carboxyhemoglobin in both arterial and peripheral venous blood and exhaled carbon monoxide in patients with acute pulmonary inflammation including bronchial asthma (n = 18) and pneumonia (n = 33), and those in patients with extrapulmonary inflammatory diseases, including acute pyelonephritis (n = 28) and active rheumatoid arthritis (n = 16). RESULTS: The values of carboxyhemoglobin in both arterial and peripheral venous blood were significantly higher in patients with pulmonary and extrapulmonary inflammation compared with those in control subjects (n = 22). Furthermore, a-vHb-CO differences in patients with inflammatory pulmonary diseases were higher than those in patients with acute pyelonephritis and patients with rheumatoid arthritis, and than those in control subjects. The a-vHb-CO differences correlated with the WBC count of peripheral venous blood in patients with pneumonia. In patients with bronchial asthma, the a-vHb-CO differences inversely correlated with FEV(1), although they did not correlate with WBC count of peripheral venous blood. The a-vHb-CO differences in patients with acute pyelonephritis were higher than those in patients with active rheumatoid arthritis. CONCLUSION: The present study suggests that a-vHb-CO differences may be a useful means to define the site of inflammation, either in the lung or organs other than the lung, in patients with a fever of unknown origin. The large a-vHb-CO differences may be caused by carbon monoxide production in pulmonary inflammation.
Effects of rhinovirus infection on the adherence of Streptococcus pneumoniae to cultured human airway epithelial cells.
To examine the effects of rhinovirus (RV) infection on the adherence of Streptococcus pneumoniae to human tracheal epithelial cells, cells were infected with RV-14, and S. pneumoniae were added to the culture medium. The number of S. pneumoniae adhering to epithelial cells increased after RV infection. Y-24180, a specific inhibitor of the platelet-activating factor receptor (PAF-R); PAF; and the pyrrolidine derivative of dithiocarbamate, an inhibitor of transcription factor nuclear factor-kappaB (NF-kappaB), decreased the number of S. pneumoniae adhering to cells after RV-14 infection. RV-14 infection increased PAF-R expression and the activation of NF-kappaB and promoter-specific transcription factor 1. These findings suggest that RV-14 infection stimulates S. pneumoniae adhesion to airway epithelial cells via increases in PAF-Rs that are partly mediated through activation of transcription factors. Increased adherence of S. pneumoniae may be one of the reasons that pneumonia develops after RV infection.
Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines.
Heme oxygenase-1 (HO-1) confers cytoprotection against oxidative stress. A (GT)n dinucleotide repeat in the 5'-flanking region of human HO-1 gene shows length polymorphism, which was classified into S (< 27 GT), M (27-32 GT), and L alleles (>/= 33 GT). Polymorphism in the HO-1 gene promoter was shown to be associated with susceptibility to pulmonary emphysema and restenosis after angioplasty. However, the biologic mechanism underlying these associations is still unclear. To examine this issue, we established lymphoblastoid cell lines (LCLs) from subjects possessing S/S or L/L genotypes. HO-1 mRNA expressions and HO activities induced by oxidative stress were significantly higher in LCLs with S/S than those with L/L. Furthermore, LCLs with S/S were significantly more resistant to oxidant-induced apoptosis than those with L/L. These findings suggested that the polymorphism of the HO-1 gene is associated with the strength of antiapoptotic effects of HO-1, resulting in an association with susceptibility to oxidative stress-mediated diseases.
Rhinovirus and asthma.
Rhinoviruses (RVs) cause the majority of common colds, which often provoke wheezing in patients with asthma. The precise mechanisms responsible for the RV infection-induced exacerbations of bronchial asthma are still uncertain. However, several reports reveal airway hyperresponsiveness, increases in chemical mediators in airway secretions such as kinin and histamine, and airway inflammation in patients with bronchial asthma after RV infection. RV infection induces an accumulation of inflammatory cells in airway mucosa and submucosa including neutrophils, lymphocytes and eosinophils. RV affects the barrier function of airway epithelial cells, and activates the airway epithelial cells and other cells in the lung to produce pro-inflammatory cytokines, including various kinds of interleukins, GM-CSF and RANTES, and histamine. RV also stimulates the expression of intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptors in the airway epithelium, receptors for major and minor RVs. On the other hand, RV infection is inhibited by treatment with soluble ICAM-1, and by reduction of ICAM-1 expression in the airway epithelial cells after treatment with erythromycin. Both soluble ICAM-1 and erythromycin were reported to reduce the frequency of common colds. Here, we review the pathogenesis and management of RV infection-induced exacerbation of bronchial asthma.
Retinoic acid inhibits elastase-induced injury in human lung epithelial cell lines.
The protective effects of retinoic acid on elastase-induced lung epithelial cell injury were studied using elastase extracted from purulent human sputum, the BEAS-2B human bronchial epithelial cell line, A549 human type II lung cell line, and primary cultures of human tracheal epithelial cells. Elastase decreased viability of BEAS-2B cells, A549 cells, and human tracheal epithelial cells in concentration- and time-dependent fashions. Elastase also induced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells detected with cell death detection enzyme-linked immunosorbent assay and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) methods. Retinoic acid alone did not affect the viability of BEAS-2B cells, A549 cells, or the tracheal epithelial cells, and did not induce apoptosis of the cells. However, retinoic acid prevented the decreases in the viability and reduced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells induced by elastase. Likewise, retinoic acid inhibited caspase 3 activity in BEAS-2B cells and A549 cells induced by elastase, as well as proteolytic activity of elastase. Furthermore, caspase 3 inhibitor inhibited the elastase-induced apoptosis of the cells. These findings suggest that retinoic acid may inhibit elastase-induced lung epithelial cell injury partly through the inhibition of proteolytic activity of elastase and through the inhibition of caspase 3 activity by elastase. Retinoic acid may, therefore, have protective effects against the elastase-induced lung injury and subsequent development of pulmonary emphysema.