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Biomedical subjects

Kiyohisa Sekizawa

Publications and source records attributed to Kiyohisa Sekizawa.

At least 19 recordsLinked to original sources
PubMed2007

Thymic and pulmonary mucosa-associated lymphoid tissue lymphomas in a patient with Sjögren's syndrome and literature review.

Mucosa-associated lymphoid tissue lymphoma (MALToma) has been reported in several organs. Among MALTomas, thymic and pulmonary MALTomas are rare. The present report describes a patient with Sjögren's syndrome who presented thymic and pulmonary MALTomas. Although the exact pathogenetic relationship between these two tumours is uncertain, it is likely that the underlying immune dysregulation related to Sjögren's syndrome contributed to the occurrence and the unusual manifestation of MALTomas in this patient.

Adult↗
PubMed2006

Transcription factors T-bet and GATA-3 regulate development of airway remodeling.

RATIONALE: Airway remodeling is an important feature of chronic asthma that causes irreversible airflow obstruction. Although asthma is considered to be a Th2 disease, the role of T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, in the pathogenesis of airway remodeling is poorly understood. OBJECTIVES: We therefore examined the effects of GATA-3 or T-bet induction of Th1/Th2 bias on the development of airway remodeling in mice. METHODS: The development of airway remodeling after repeated allergen challenges was analyzed using transgenic mice overexpressing either GATA-3 or T-bet. MAIN RESULTS: The degrees of subepithelial fibrosis and airway smooth muscle hyperplasia after repeated allergen exposure were significantly enhanced in mice overexpressing GATA-3, compared with wild-type mice. Allergen-induced goblet cell hyperplasia and mucus hypersecretion were significantly lower in mice overexpressing T-bet than in wild-type mice. Eosinophilic airway inflammation increased in mice overexpressing GATA-3, but decreased in mice overexpressing T-bet after repeated allergen exposure. Cytokine analysis revealed that the Th1/Th2 cytokine balance shifted to Th2 in lung homogenates and lung T cells of mice overexpressing GATA-3, whereas this balance shifted to Th1 in those of mice overexpressing T-bet after allergen exposure. Lung transforming growth factor-beta and eotaxin levels were associated with the degree of subepithelial fibrosis and eosinophilic airway inflammation, respectively. CONCLUSIONS: Overall, the results indicate that development of airway remodeling is regulated by the lung Th1/Th2 bias induced by GATA-3 and T-bet.

Animals↗
PubMed2006

Effect of diesel exhaust particles on mRNA expression of viral and bacterial receptors in rat lung epithelial L2 cells.

Epidemiological studies have shown that particulate matter (PM) is associated with adverse respiratory health effects. Although infection in the respiratory organ is one of the most important health risks the association of infection with PM is not fully understood. As we had hypothesized that diesel exhaust particles (DEP), one of the major component of PM, may induce the expression of receptors for viruses and bacteria at invasion sites, we studied the effect of DEP on the mRNA expression of intercellular adhesion molecule-1 (ICAM-1), low-density lipoprotein (LDL) and platelet-activating factor (PAF) receptors, which are invasion sites of virus and bacteria, on rat lung epithelial cells. The real-time quantitative polymerase chain reaction (PCR) method was used for the evaluation. All of these mRNAs were up-regulated by 3, 10, and 30 microg/ml of DEP in a concentration-dependent manner. The up-regulation of each was associated with the mRNA expression of heme oxygenase-1 (HO-1), a marker of oxidative stress. Our present results show that DEP up-regulated the mRNA expression of viral and bacterial receptors. This up-regulation might be associated with DEP-induced oxidative stress. These results thus suggest that DEP may enhance the risk of pneumonia by increasing the density of bacterial and viral invasion sites in the lungs.

Air Pollutants↗
PubMed2006

Effect of inhaled steroids on increased collagen synthesis in asthma.

BACKGROUND: We previously reported that sputum levels of procollagen type I C-terminal peptide (PICP), a marker of ongoing collagen type I deposition, are increased in proportion to airway inflammation in asthma patients. OBJECTIVES: In this study, we examined the effect of inhaled corticosteroids on increased collagen synthesis in step 2-4 asthmatics. METHODS: We compared the sputum PICP concentrations of 25 steroid-naive asthmatics, 25 normal volunteers, and 10 subjects with chronic obstructive pulmonary disease. Asthma subjects were also instructed to start fluticasone propionate treatment, and the percentage of forced expiratory volume in 1 s, sputum eosinophil counts, sputum PICP concentrations, and sputum transforming growth factor-beta-positive cell counts before treatment were compared with those 1 month after treatment. RESULTS: Sputum PICP concentrations were detected in the following order: asthma group >or= chronic obstructive pulmonary disease group > control group. Asthma patients showing high sputum PICP belonged to step 4, although there was no correlation between sputum PICP and asthma severity. Treatment with fluticasone propionate not only significantly improved the mean percentage of forced expiratory volume in 1 s (from 66.7 to 87.2%), but also decreased the mean sputum eosinophil counts (from 13.4 to 5.8%), the mean sputum PICP concentrations (from 30.8 to 10.2 ng/ml), and the mean sputum tumor growth factor-beta-positive cells (from 11.3 to 2.8%). Nevertheless, a significant difference in sputum PICP concentrations was still observed between the control group and the steroid-treated asthma group. CONCLUSIONS: The present results suggest that inhaled corticosteroid treatment might reduce sputum indexes of collagen metabolism and eosinophilic inflammation in asthma patients.

Administration, Inhalation↗
PubMed2006

Anaerobic bacterial empyema accompanying intrathoracic gas formation in anorexia nervosa.

OBJECTIVE: Intrathoracic gas formation due to anaerobic pleuropulmonary infection is rare. METHOD & RESULTS: We experienced a case of empyema with intrathoracic gas formation by an anaerobic bacterium in a young woman with anorexia nervosa (AN). CONCLUSION: We should therefore be alert to the possibility of serious infection in patients with AN, even when they have few complaints or normal white blood cell counts.

Adult↗
PubMed2006

Prospective study of fever and pneumonia after flexible fiberoptic bronchoscopy in older people.

OBJECTIVES: To assess the frequency of fever and pneumonia after fiberoptic bronchoscopy (FOB) in older people and to evaluate increased risk for these two adverse events with increasing age. DESIGN: Prospective study. SETTING: University hospital system. PARTICIPANTS: Three hundred fifty-eight patients, with 165 (46.1%) patients aged 70 and older, undergoing bronchoscopy. MEASUREMENTS: Indications, abnormal bronchoscopic findings, sampling procedures, final diagnosis, and fever and pneumonia after bronchoscopy. RESULTS: With regard to the indication for bronchoscopy and abnormal bronchoscopic findings, there was no statistical difference between elderly patients (> or =70) and younger patients (<70). Procedures such as forceps biopsy, brushing, and curetting were not performed more often in elderly patients, although final diagnosis of lung cancer was significantly more common in the elderly group (P=.002). The overall incidence of fever after FOB was 6.7%, and that of pneumonia after FOB was 5.6%. The patients aged 70 and older had an incidence of fever after FOB of 3.6% and an incidence of pneumonia of 4.2%, which were not higher than those in patients younger than 70. CONCLUSION: Increasing age is not associated with increasing fever and pneumonia after FOB, and chronological age should not be considered a limiting factor in the decision of whether to perform FOB when it is clinically indicated.

Adult↗
PubMed2006

Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy.

PURPOSE: Radiation pneumonitis (RP) is a serious complication in patients undergoing thoracic radiotherapy (TRT). Serum KL-6 and SP-D have been shown to increase in several kinds of interstitial pneumonia. To evaluate their clinical usefulness in detecting RP, we serially measured them in patients receiving TRT. MATERIALS AND METHODS: Thirty-nine patients, who received TRT for lung cancer between July 1999 and April 2004, were prospectively studied. Serum levels of KL-6 and SP-D were measured using enzyme-linked immunosorbent assays. Patients were followed up until August 2004 or their deaths. RESULTS: During the period, RP occurred in 19 patients. In five patients with diffuse RP extended outside the radiation field, serum KL-6 levels increased, reaching more than 1,000 U/mL. Serum KL-6 levels at 40 Gy in patients who developed RP were higher than those without it (p = 0.0363, Mann-Whitney U test). In addition, serum KL-6 levels at 40 Gy in patients who developed RP were higher than those of pretreatment (p = 0.0126, Wilcoxon signed rank test). On the other hand, there were no statistical differences between sp-d at 40 Gy and those before TRT (P = 0.1165). CONCLUSIONS: Increased KL-6 at 40 Gy compared with those before treatment in patients undergoing TRT may be of clinical significance. KL-6 proved to be a useful indicator for estimating RP, while usefulness of SP-D was not confirmed in this study.

Aged↗
PubMed2006

Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis.

Recent studies have demonstrated that Th2 cytokines, such as interleukin-4 and interleukin-13, enhance fibrotic processes by activating fibroblast proliferation and collagen production, whereas interferon-gamma, a Th1 cytokine, inhibits these processes. Th1 and Th2 cells both differentiate from common T precursor cells, with transcription factor GATA-3 a key regulator of Th2 differentiation. In the present study, therefore, we examined the effects of GATA-3 overexpression on the development of pulmonary fibrosis in a mouse model. Wild-type C57BL/6 mice and GATA-3-overexpressing (GATA-3-tg) mice of the same background were intratracheally treated with bleomycin. The survival rate after bleomycin was significantly decreased in GATA-3-tg mice compared with wild-type mice. The degree of pulmonary fibrosis was much greater in GATA-3-tg mice than in wild-type mice 28 days after bleomycin treatment. Lung interferon-gamma concentration was significantly decreased in GATA-3-tg mice compared with wild-type mice by 7 days after either saline or bleomycin treatment. The concentration of transforming growth factor-beta, a fibrogenic cytokine, was significantly higher in GATA-3-tg mice than in wild-type mice. Exogenous administration of interferon-gamma to GATA-3-tg mice improved the degree of pulmonary fibrosis and thus increased survival. These results indicate that overexpression of GATA-3 enhances the development of pulmonary fibrosis, possibly by reducing interferon-gamma levels in the lung.

Animals↗
PubMed2006

MMP14 gene polymorphisms in chronic obstructive pulmonary disease.

Proteinase/antiproteinase imbalance is a widely accepted theory for the pathogenesis of COPD. Among various proteinases, matrix metalloproteinases (MMPs) digest extracellular matrix of the lung and play significant roles in the development of COPD. Polymorphisms of an MMP that upregulate its activity may result in the degradation of the lung matrix. A case-control study was performed to investigate the association of polymorphisms of the MMP14 gene with COPD. Japanese subjects (96 COPD patients and 61 controls) and Egyptian subjects (106 COPD patients and 72 controls) were recruited. Each subject was genotyped for seven single nucleotide polymorphisms (SNPs) of the MMP14 gene; -165 G/T and -72 G/A in the promoter region, +221 C/T in exon 1, +6727 C/G and +6767 G/A in exon 5, +7096 T/C in exon 6, and +8153 G/A in exon 8. The distributions of the genotype frequencies of these SNPs were not significantly different between the COPD patients and the controls in either ethnic group after correction of multiple comparisons. In the haplotype analysis, however, the haplotype -165 T : +221 T : +6727 C : +7096 C had a significantly higher frequency in the Egyptian COPD group than the control group (pcorr = 0.0063). The haplotype of the MMP14 gene, -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of COPD.

Aged↗
PubMed2006

Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: relationship to interleukin 13 gene polymorphism.

Activation of the cyclic AMP (cAMP) signaling pathway leads to the suppression of inflammation in the airways and relaxation of airway smooth muscle. Intracellular cAMP levels are determined by a balance between the activities of adenylate cyclase and phosphodiesterases. We hypothesized that polymorphisms of the phosphodiesterase 4D (PDE4D) gene activate its protein function which leads to the downregulation of cAMP, resulting in the development of chronic obstructive pulmonary disease (COPD). A case-control study was performed using Japanese (96 COPD patients and 61 controls) and Egyptians (106 COPD patients and 72 controls) to investigate the association between the polymorphisms of the PDE4D gene and the development of COPD. Genotyping of all subjects for SNP7 (dbSNP ID, rs10075508), SNP13 (rs829259) and SNP15 (rs702531) in exon 15 of the PDE4D gene was conducted. Furthermore, the distributions of haplotypes consisting of PDE4D polymorphisms and those of interleukin (IL) 4, IL13 and beta2 adrenoceptor were analyzed. The distribution of SNP13 allele frequencies of the PDE4D gene was significantly different between the COPD and control groups in the Japanese population (p = 0.041). In haplotype analysis, haplotypes composed of PDE4D SNP7 and IL13 +2044 G/A in the Japanese population showed significant difference between the patients and controls (pcorr = 0.00048). Thus, SNP13 and haplotypes, SNP7 G/A and IL13 +2044 G/A, may be useful for predicting COPD susceptibility.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells.

Mucus hypersecretion relates to exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD) caused by rhinovirus (RV) infection. We examined the mechanisms of RV infection-induced mucin production in human tracheal surface epithelial cells and submucosal gland cells. RV14 up-regulated the mRNA expression of MUC2, MUC3, MUC5AC, MUC5B and MUC6, and increased MUC5AC and total mucin concentration in supernatants and lysates of the surface cells. An inhibitor of the nuclear factor kappaB caffeic acid phenylethyl ester, inhibitors of selective p44/42 mitogen-activated protein kinase-kinase PD98059 and U0126, and a selective Src inhibitor PP1 attenuated MUC5AC mRNA expression, and secretion and production of MUC5AC and total mucin glycoprotein in the surface cells. In the gland cells, RV14 also increased mRNA expression of MUC2, MUC5AC, MUC5B and MUC7, and the inhibitors attenuated the secretion of total mucin glycoprotein. Src-related p44/42 mitogen-activated protein kinase pathway may be associated with RV-induced mucin hypersecretion in human airways.

Aged↗
PubMed2005

Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema.

Emphysema is one of the major pathological abnormalities associated with chronic obstructive pulmonary disease. The protease/antiprotease imbalance and inflammation resulting from oxidative stress have been attributed to the pathogenesis of emphysema. Nrf2 is believed to protect against oxidative tissue damage through the transcriptional activation of a battery of antioxidant enzymes. In this study, we investigated the protective role of Nrf2 in the development of emphysema using elastase-induced emphysema as our model system. We found that elastase-provoked emphysema was markedly exacerbated in Nrf2-knockout (KO) mice compared with wild-type mice. The severity of emphysema in Nrf2-KO mice correlated intimately with the degree of lung inflammation in the initial stage of elastase treatment. The highly inducible expression of antioxidant and antiprotease genes observed in wild-type alveolar macrophages was significantly attenuated in the lungs of Nrf2-KO mice. Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes. Thus, Nrf2 appears to exert its protective effects through the transcriptional activation of antiprotease and antioxidant genes in alveolar macrophages.

Animals↗
PubMed2005

The effect of smoking-related hyperhomocysteinemia on spirometric declines in chronic obstructive pulmonary disease in elderly Japanese.

Smoking is implicated in chronic obstructive pulmonary disease (COPD) and hyperhomocysteinemia. To elucidate the role of hyperhomocysteinemia in COPD, we examined the relationship between plasma total homocysteine (tHcy) and spirometric declines in patients with COPD. We recruited 7 male never-smokers, 16 male control smokers, and 24 male patients with COPD. We investigated whether or not smoking might induce hyperhomocysteinemia in subjects predisposed to COPD, and then prospectively examined the relationship between plasma tHcy concentration and annual decline in FEV(1.0) in the COPD group. We found that plasma tHcy concentrations declined among groups in the following order: COPD group > control group > never-smoker group. Furthermore, plasma tHcy concentrations in the COPD group were significantly correlated with %FEV(1.0) (r(s) = 0.46). Also, COPD patients with severe airflow limitation showed a significant decrease in PaO2, which might be involved in the decreased tHcy in those patients. The prospective analysis revealed that plasma tHcy concentration, but not a history of smoking, were significantly correlated with the annual decline in FEV(1.0) calculated by the difference in FEV(1.0) between the first examination and an examination the following year (r(s) = 0.40). The present study suggests that smoking might increase plasma tHcy concentrations, leading to spirometric declines in subjects predisposed to COPD.

Aged↗
PubMed2005

Polymorphisms of TNFalpha, IL1beta, and IL1RN genes in chronic obstructive pulmonary disease.

It is recognized that genetic factors play a role in the susceptibility to COPD. COPD is characterized by airflow limitation. Chronic inflammation causes small airway disease and parenchymal destruction, leading to the airflow limitation. Polymorphisms in pro-inflammatory cytokine genes may confer a risk for the development of COPD. A case-control association study was performed in Japanese population (88 COPD patients and 61 controls) and Egyptian population (106 patients and 72 controls). Genotype and allele frequencies of the TNFalpha -308 G/A and +489 G/A polymorphisms, the IL1beta -511 C/T, -31 T/C, and +3954 C/T polymorphisms, and a VNTR polymorphism in intron 2 of the IL1RN gene were investigated. In addition, pairwise haplotype frequencies were analyzed. When studied independently, none of the polymorphisms were associated with the development of COPD in both populations. However, in the Egyptian population, the distributions of the haplotype (IL1beta -31 T/C : IL1beta +3954 C/T) were significantly different between the COPD patients and the controls (p(corr)=0.0037). Our findings suggest that this haplotype within the IL1beta gene may be involved in the pathogenesis of COPD and that the genetic factors of COPD susceptibility might be different between different populations.

Aged↗
PubMed2005

Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury.

RATIONALE: Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes. OBJECTIVES: Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2. METHODS: To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2. MAIN RESULTS: We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes. CONCLUSIONS: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Animals↗