Toyohiro Hirai

Kyoto University, Kioto, Kyōto, Japan

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Publications (108)336 Total impact

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    ABSTRACT: BACKGROUND: Matrix metalloproteinases (MMPs) are believed to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and MMP-7 has been described as a useful biomarker for IPF. However, little is known regarding the significance of MMP-10 as a biomarker for IPF. METHODS: This observational cohort study included 57 patients with IPF. Serum MMPs were comprehensively measured in all patients, and the relationships between these markers and both disease severity and prognosis were evaluated. Bronchoalveolar lavage fluid (BALF) MMP-7 and -10 levels were measured in 19 patients to investigate the correlation between these markers and their corresponding serum values. Immunohistochemical staining for MMP-10 was also performed in IPF lung tissue. RESULTS: Serum MMP-7 and -10 levels correlated significantly with both the percentage of predicted forced vital capacity (ρ = -0.31, p = 0.02 and ρ = -0.34, p < 0.01, respectively) and the percentage of predicted diffusing capacity of the lung for carbon monoxide (ρ = -0.32, p = 0.02 and ρ = -0.43, p < 0.01, respectively). BALF MMP-7 and -10 levels correlated with their corresponding serum concentrations. Only serum MMP-10 predicted clinical deterioration within 6 months and overall survival. In IPF lungs, the expression of MMP-10 was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. CONCLUSIONS: MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF.
    Respiratory Research 09/2016; 16(1). DOI:10.1186/s12931-015-0280-9 · 3.09 Impact Factor
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    ABSTRACT: Background: Decreased bone mineral density (BMD) has been reported in patients with interstitial lung disease. However, BMD has not been evaluated in steroid-naïve patients with idiopathic pulmonary fibrosis (IPF). We aimed to measure vertebral BMD and investigate its relationship with clinical features in steroid-naïve patients with IPF. Methods: We recruited 55 consecutive male patients with steroid-naïve IPF; 55 male smokers without chronic obstructive pulmonary disease or interstitial lung disease, matched by age, body mass index, and pack-years of smoking (control smokers); and 27 healthy young adults. Thoracic vertebral BMD was measured by computed tomography (CT). We further investigated the relationship of BMD with clinical features and quantitative CT indices of lung density in patients with IPF. Results: The thoracic vertebral BMD of patients with IPF was significantly lower than that of control smokers (139.9 ± 28.5 mg/mL vs 160.9 ± 39.5 mg/mL, p < 0.01). Fifteen patients (27.2%) had BMD more than 2.5 SD below the mean BMD of young adults. In patients with IPF, emphysema volume (EV) and its ratio to total lung volume (EV%) had a significantly negative correlation with BMD (r = -0.28, p = 0.04 and r = -0.39, p < 0.01, respectively). In stepwise multiple regression analysis, EV% was an independent explanatory variable for thoracic vertebral BMD. Conclusion: A substantial percentage of steroid-naïve IPF patients had decreased BMD, and a significant association was observed between the extent of emphysema and BMD in IPF.
    Respiratory medicine 09/2015; 109(9):1181-7. DOI:10.1016/j.rmed.2015.06.014 · 3.09 Impact Factor
  • Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 07/2015; · 3.05 Impact Factor
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    ABSTRACT: Background Quantitative computed tomography (CT) analysis has been proposed as a means of objectively assessing fibrotic interstitial pneumonia (IP) including idiopathic pulmonary fibrosis (IPF). We investigated whether percentages of high-attenuation areas (HAA%) and cystic areas (CA%) quantified from CT images were useful as indices of fibrotic IP. Methods CT images of 74 patients with fibrotic idiopathic interstitial pneumonias (IPF, 36; non-specific interstitial pneumonia, 9; unclassifiable idiopathic interstitial pneumonia, 29) were analyzed via in-house computer software, which automatically calculated HAA%, CA%, mean lung density (MLD), standard deviation of lung density (SD-LD), kurtosis, and skewness from CT attenuation histograms. These indices were compared in each instance with physiologic measures, visual fibrosis score, clinical diagnosis, radiologic CT pattern, and prognosis. Results HAA% correlated significantly with physiologic measures and visual fibrosis score to a moderate extent (%forced vital capacity, rs = −0.59; % carbon monoxide diffusion capacity, rs = −0.43; fibrosis score, rs = 0.23). Densitometric parameters (MLD, SD-LD, kurtosis, and skewness) correlated significantly with physiologic measures and fibrosis score (|rs| = 0.28-0.59). CA% showed no association with pulmonary functions but differed significantly between IPF and other interstitial pneumonias (IPs) (1.50 ± 2.41 % vs. 0.41 ± 0.80 %; P < 0.01) and between the definite usual interstitial pneumonia (UIP) pattern and other patterns (1.48 ± 2.38 % vs. 0.55 ± 1.19 %; P < 0.01). On univariate analysis, HAA%, MLD, SD-LD, kurtosis, skewness, fibrosis score, and definite UIP pattern all correlated with survival, with kurtosis alone identified as a significant predictor of mortality on multivariate analysis (hazard ratio = 0.67; 95 % CI, 0.44-0.96; P = 0.03). Conclusion CA% and HAA% are novel quantitative CT indices with differing properties in fibrotic IP evaluations. HAA% largely reflects physiologic impairments, whereas CA% corresponds with diagnosis and HRCT pattern. Of the CT indices examined, kurtosis constituted the strongest predictor of mortality.
    BMC Pulmonary Medicine 07/2015; 15(1). DOI:10.1186/s12890-015-0069-0 · 2.40 Impact Factor
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    ABSTRACT: Airway remodelling in bronchial asthma (BA) and COPD has been quantitatively assessed by analysing the airway wall area and the luminal area on cross-sectional CT images. To date, there have been no reports on assessment of the longitudinal structure of the airway lumen. Quantitative airway analysis using CT was performed on three groups consisting of 29 patients with BA, 58 patients with COPD and 59 healthy controls. To assess the longitudinal shape irregularity of the airway lumen, new quantitative CT parameters, validated by a phantom study, were established. The internal radii of imaginary inscribed spheres in the airway lumen were measured as a function of distance from the level of the carina to the fifth-order branches of the right posterior basal bronchus. The gaps of these radii from the regression line were calculated as parameters to reflect the longitudinal airway lumen shape irregularity. These new parameters were compared among the study groups as well as with the conventional parameters of airway wall thickening and luminal area. Longitudinal airway lumen shape irregularity was significantly greater in patients with COPD than in those with BA and healthy controls. Wall thickening was significantly greater, and luminal area smaller, in patients with BA than in those with COPD and healthy controls. These results were consistent even among the BA and COPD subgroups with similar airflow limitation. The combination of cross-sectional and longitudinal airway structure analyses using CT images may suggest differences in the characteristics of airway remodelling between COPD and asthma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Thorax 05/2015; 70(8). DOI:10.1136/thoraxjnl-2014-206651 · 8.29 Impact Factor
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    ABSTRACT: Computed tomography (CT) assessment of air trapping has been considered useful as a measure of small airway disease. Mean lung density (MLD) and the percentage of the lung field occupied by low attenuation area (LAA%) can be evaluated automatically, and their expiratory/inspiratory (E/I) ratios correlate with asthma severity and spirometry parameters. However, mosaic attenuation, another indicator of air trapping, has been assessed visually, and its functional relevance remains controversial. This retrospective study was conducted to correlate mosaic attenuation, which was assessed visually and automatically, and the E/I ratios of MLD and LAA% (defined as areas <-960 Hounsfield units) with clinical and physiological variables, including impulse oscillometry (IOS) indices. In 36 nonsmoking patients with stable asthma, the lungs were scanned at full inspiration and full expiration. Mosaic attenuation was measured visually and automatically, by counting areas with CT values higher than the surrounding areas. MLD and LAA% were measured using our validated method. Spirometry, IOS, exhaled NO and the sputum eosinophil count were evaluated. The automatic results and visual scores of mosaic attenuation correlated well on expiratory scans (r = 0.894) and to a lesser degree on inspiratory scans (r = 0.629; p < 0.0001 for both). However, only the E/I ratios of MLD and LAA% correlated with forced expiratory volume in 1 s/forced vital capacity of spirometry and the IOS indices of resistance from 5 to 20 Hz and the integrated area of low-frequency reactance. Our automatic method for analysis of mosaic attenuation is likely useful, but the results themselves may not be reflecting small airway involvement of asthma, unlike the E/I ratios of MLD and LAA%. © 2015 S. Karger AG, Basel.
    Respiration 04/2015; 89(6). DOI:10.1159/000381553 · 2.59 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by a mixture of emphysema and airway disease. The forced oscillation technique (FOT) has been applied to COPD patients to clarify changes in respiratory mechanics; dynamic changes in respiratory resistance (Rrs) during breathing (within-breath changes in Rrs, ΔRrs) are characteristic of COPD. However, the pathophysiological significance of these changes is unknown. The aim of this study was to assess how emphysema and airway disease influence ΔRrs in COPD patients. In this cross-sectional study, stable COPD patients were recruited and underwent respiratory impedance measurements with a commercially available FOT device. Rrs was recorded during tidal breathing and then analyzed as whole-breath Rrs (Rrs at 5 Hz, R5; Rrs at 20 Hz, R20; and their difference, R5-R20) or as ΔRrs, the difference between the expiratory and inspiratory Rrs (ΔR5, ΔR20 and ΔR5-R20). The percentage of the low attenuation area (LAA%) and airway wall area (WA%) was quantified by computed tomography analysis, and their contributions to ΔRrs were examined. Seventy-five COPD patients were recruited. LAA% was negatively correlated with ΔR5 and ΔR5-R20 (P = 0.0002 and P = 0.0033, respectively); meanwhile, WA% in B(10) was positively correlated with ΔR5 and ΔR5-R20 (P = 0.0057 and P < 0.0001, respectively). Multivariate analysis revealed that the contribution of both LAA% and WA% in B(10) to ΔRrs was independent of the severity of airflow limitations. This study shows that emphysema suppresses ΔRrs in COPD patients, while airway disease increases ΔRrs in these patients. © 2015 Asian Pacific Society of Respirology.
    Respirology 03/2015; 20(5). DOI:10.1111/resp.12535 · 3.35 Impact Factor
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    ABSTRACT: This study was conducted to evaluate trends in the isolation of strains of nontuberculous mycobacteria (NTM) and trends in the number of patients with pulmonary Mycobacterium avium complex (MAC) disease. We retrospectively reviewed microbiological results and clinical data to identify patients who were diagnosed with pulmonary MAC disease at Kyoto University Hospital in Japan between 2000 and 2013. NTM were isolated from 6,327 of 80,285 samples (7.9%) for mycobacterial culture. The proportion of NTM isolates among all mycobacterial isolates increased from 355 of 792 samples (44.8%) in 2000 to 688 of 847 samples (81.2%) in 2013. MAC was most frequently observed (5436 isolates, 85.9%), followed by M. abscessus (175 isolates, 2.8%) and M. kansasii (74 isolates, 1.2%). A total of 592 patients with pulmonary MAC disease were identified (age, 66.0±11.5 years; females, 61.1%). Compared with the early cohort (2000-2006, 236 patients), more patients in the late cohort (2007-2013, 356 patients) had an underlying disease (157 [66.5%] vs. 284 [79.8%], P=0.0003), a Charlson comorbidity index score ≥1 (115 [48.7%] vs. 213 [59.8%], P=0.008), collagen vascular disease (18 [7.6%] vs. 60 [16.9%], P=0.001), rheumatoid arthritis (11 [4.7%] vs. 41 [11.5%], P=0.004), and used immunosuppressive drugs (22 [9.3%] vs. 63 [17.7%], P=0.004). The numbers of patients with lung disease, malignant disease and diabetes mellitus increased; however, their frequencies did not differ. The recovery rate of NTM and patients with pulmonary MAC disease increased, especially in patients with collagen vascular disease or rheumatoid arthritis or who used immunosuppressive drugs.
    Journal of Infection and Chemotherapy 01/2015; 21(5). DOI:10.1016/j.jiac.2015.01.004 · 1.49 Impact Factor
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    ABSTRACT: Objectives: 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was reported to be useful for monitoring immunoglobulin G4-related disease (IgG4-RD); however, a quantitative FDG-PET/CT analysis such as total lesion glycolysis (TLG) has not yet been conducted. This study aimed to investigate whether TLG would correlate with serum markers in IgG4-RD, and the utility of TLG for disease monitoring. Methods: This retrospective study included 17 patients (12 men; median age, 62 years) who were followed up at Kyoto University Hospital and underwent FDG-PET/CT from April 2009 to November 2013. TLG was calculated for the involved lesions. Correlations between serum markers [IgG4, soluble IL-2 receptor (sIL-2R), lactate dehydrogenase (LDH), and C-reactive protein (CRP)] and TLG concomitant with FDG-PET/CT scans were investigated. Serial changes in TLG were assessed in patients who underwent follow-up FDG-PET/CT (n = 6). Results: The calculated median (IQL) TLG value was 154.8 (63.7-324.4). A significant correlation was found between the sIL-2R level and TLG (P = 0.001, rs = 0.763). In contrast, no correlations were found between the IgG4, LDH, or CRP levels and TLG. Increased or decreased TLG corresponded with clinical disease improvement or worsening. Conclusions: TLG correlated significantly with the serum sIL-2R level and may be useful for disease monitoring in IgG4-RD.
    Modern Rheumatology 12/2014; 25(4):1-22. DOI:10.3109/14397595.2014.990674 · 2.40 Impact Factor
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    ABSTRACT: Background Environmental exposure is a likely risk factor for the development of pulmonary Mycobacterium avium complex (MAC) disease. The influence of environmental exposure on the response to antimicrobial treatment and relapse is unknown. Methods We recruited 72 patients with pulmonary MAC disease (male [female], 18 [54]; age, 61.7 ± 10.3 years) who initiated and completed standard three-drug regimens for more than 12 months between January 2007 and December 2011. The factors associated with sputum conversion, relapse and treatment success without relapse were retrospectively evaluated after adjustments for confounding predictors. Results Fifty-two patients (72.2%) demonstrated sputum conversion, and 15 patients (28.8%) relapsed. A total of 37 patients (51.4%) demonstrated treatment success. Sputum conversion was associated with negative smears (odds ratio [OR], 3.89; 95% confidence interval [CI], 1.27-12.60; P = 0.02). A relapse occurred in patients with low soil exposure after the start of treatment less frequently than in patients with high soil exposure (7/42 [16.7%] vs. 8/10 [80.0%], P = 0.0003). Treatment success was associated with low soil exposure after the beginning of treatment (OR, 13.46; 95% CI, 3.24-93.43; P = 0.0001) and a negative smear (OR, 2.97; 95% CI, 1.02-9.13; P = 0.047). Conclusion Low soil exposure was independently associated with better microbiological outcomes in patients with pulmonary MAC disease after adjusting for confounding clinical, microbiological and radiographic findings.
    BMC Infectious Diseases 09/2014; 14(1):522. DOI:10.1186/1471-2334-14-522 · 2.61 Impact Factor
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    ABSTRACT: No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1(+) "ventralized" anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM(+) cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM(+) cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine.
    Stem Cell Reports 09/2014; 3(3). DOI:10.1016/j.stemcr.2014.07.005 · 5.37 Impact Factor
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    ABSTRACT: Since commercial forced oscillation technique (FOT) devices became available, they have been widely used for physiological assessments, mainly of obstructive lung diseases. However, it is not known whether the impedance values measured with different devices are identical. In this study, two FOT devices-the impulse oscillometry system (IOS) and the MostGraph (MG)-were compared using phantom models. The resistance values varied up to 10 % from estimated values in both devices. Additionally, there was a difference in frequency dependence for the resistance between the devices. The reactance values measured with MG were higher than those measured with IOS. The effects of ventilation on the measured impedance values were higher for IOS than for MG, especially at lower frequencies. We concluded that the devices do not always generate identical impedance values. Thus, differences between the devices should be taken into consideration when evaluating clinical data.
    The Journal of Physiological Sciences 07/2014; 64(5). DOI:10.1007/s12576-014-0329-4 · 1.90 Impact Factor
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    ABSTRACT: Bacteria and viruses are major causes of chronic obstructive pulmonary disease (COPD) exacerbations. Molecular components of these pathogens are recognized by pattern-recognition receptors (PRRs) expressed by various cells in the airway, which leads to initiation of inflammatory processes. Expression levels of PRRs in airway inflammatory cells are expected to affect susceptibility to COPD exacerbation. This prospective observational study was conducted to detect any association between exacerbation and PRR expression. Thirty-one male COPD patients were recruited. At baseline, clinical history, lung function measurements, peripheral blood samples and induced sputum were obtained. Using sputum samples, we performed gene expression analysis of TLR2, TLR3, TLR4, NOD1, NOD2, RIG-I and MDA-5 by quantitative reverse transcription-polymerase chain reaction in addition to quantitative bacterial culture. COPD exacerbations were assessed based on Anthonisen's criteria using symptom diaries for the following 1-year period. During 1-year follow-up period, 13 patients experienced at least one exacerbation, but 18 patients did not. Those with exacerbations tended to be more severe COPD and showed larger neutrophil fraction in their induced sputum. Among PRRs, only TLR3 gene expression was increased in COPD patients with exacerbation compared with those without exacerbations. Multivariate logistic regression analysis including neutrophil fraction and TLR3 gene expression as predictor variables demonstrated that only an increase of neutrophil fraction, but not TLR3 gene expression, was a significant predictor for COPD exacerbation. TLR3 expression in inflammatory cells might affect the susceptibility to COPD exacerbation.
    The Clinical Respiratory Journal 06/2014; DOI:10.1111/crj.12171 · 1.51 Impact Factor
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    ABSTRACT: Background There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure. Methods In acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains: C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury. Results Acute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2, protein levels of KC, MIP-1α, IL-1β, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure. Conclusions Cigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease.
    BMC Pulmonary Medicine 05/2014; 14(1):79. DOI:10.1186/1471-2466-14-79 · 2.40 Impact Factor
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    ABSTRACT: Patients with pulmonary Mycobacterium avium complex (MAC) disease are often co-infected with various pathogenic microorganisms. This study aimed to determine the prevalence of co-infection with non-MAC pathogens and the risk factors associated with co-infection in patients with pulmonary MAC disease. We retrospectively reviewed the patient characteristics, microbiological results and chest CT findings in 275 patients with pulmonary MAC who visited the Kyoto University Hospital from January 2001 to May 2013. We defined chronic pathogenic co-infection as the isolation of non-MAC pathogens from sputum samples taken on more than two visits that occurred at least 3 months apart. The participants were predominantly female (74.5%) and infected with M. avium (75.6%). Chronic co-infection with any pathogen was observed in 124 patients (45.1%). Methicillin-sensitive Staphylococcus aureus (MSSA; n=64), Pseudomonas aeruginosa (n=35) and Aspergillus spp (n=18) were the most prevalent pathogens. The adjusted factors were chronic obstructive pulmonary disease (COPD; OR=4.2, 95% CI 1.6 to 13.1) and pulmonary M. intracellulare disease (OR=2.2, 95% CI 1.1 to 4.4) in chronic co-infections; COPD (OR=4.2, 95% CI 2.1 to 31.4), long duration of MAC disease (OR=2.2, 95% CI 1.2 to 4.4) and nodules (OR=3.5, 95% CI 1.2 to 13.2) in chronic MSSA co-infection; COPD (OR=7.5, 95% CI 2.1 to 31.4) and lower lobe involvement (OR=9.9, 95% CI 2.0 to 90.6) in chronic P. aeruginosa co-infection; and use of systemic corticosteroids (OR=7.1, 95% CI 1.2 to 50.9) and pulmonary M. intracellulare disease (OR=4.0, 95% CI 1.1 to 14.5) in chronic Aspergillus spp co-infection. Patients with pulmonary MAC disease frequently had chronic co-infections with pathogenic microorganisms such as MSSA, P. aeruginosa and Aspergillus. The risk factors for chronic co-infection were COPD and pulmonary M. intracellulare disease.
    05/2014; 1(1):e000050. DOI:10.1136/bmjresp-2014-000050
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    ABSTRACT: To the Editor:Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kD lipocalin that is covalently bound to matrix metalloproteinase (MMP)-9 produced by neutrophils (1). NGAL in blood or bronchoalveolar lavage fluid (BALF) may reflect neutrophilic inflammation in the lungs (2, 3), and it is highly induced in injured epithelial cells, including those in the lung (4). Possible roles for neutrophilic inflammation and epithelial injury have been reported in idiopathic pulmonary fibrosis (IPF). Thus, we hypothesised that NGAL may be associated with the pathogenesis of IPF. To investigate the roles of NGAL in IPF, we used immunohistochemical staining for lung specimens and measured plasma and BALF NGAL levels. Our study was approved by the Ethics Committee of Kyoto University (approval No. E438), and written informed consent was obtained from all study participants.First, we immunohistochemically stained the lung tissue specimens of six IPF patients, two nonspecific interstitial pneumonia (NSIP) patients, and a control (normal area distant from the lesion of surgically diagnosed organising pneumonia) for NGAL using a conventional method (5). We also performed sequential immunofluorescent staining for NGAL and MMP-9. Immunohistochemical staining showed that NGAL was abundantly expressed in airway epithelial cells that covered the honeycomb cysts in IPF (fig. 1a and b). Further, histologically.
    European Respiratory Journal 02/2014; 43(6). DOI:10.1183/09031936.00192613 · 7.64 Impact Factor
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    ABSTRACT: Rationale: Polyclonal and mixed mycobacterial Mycobacterium avium complex (MAC) infection is observed in pulmonary MAC disease. Human living environments contain multiple species or genotypes of non-tuberculous mycobacterial strains and are considered sources of infection. Objectives: To investigate the association of environmental exposure with polyclonal and mixed mycobacterial infection in pulmonary MAC disease after adjustments for potential confounding diseases and conditions, and radiographic findings. Methods: We collected two separate sputum samples from 102 patients and single sputum samples from 18 patients in whom the second MAC strain was not isolated in our prospective cohort of pulmonary MAC disease. MAC isolates from sputum samples and patients' residential soils were used for variable number of tandem repeats (VNTR) analyses. Polyclonal and mixed mycobacterial MAC infections were defined as having different VNTR genotypes and other mycobacterial species, respectively. Monoclonal MAC infection was defined as all isolates showing a single VNTR genotype. Associations of the type of infection with clinical and radiographic findings, and environmental exposure were measured. Measurements and Main Results: Polyclonal and mixed mycobacterial MAC and monoclonal infections were observed in 42 and 78 patients, respectively. By stepwise regression analysis, patients with polyclonal and mixed mycobacterial MAC infections were associated with history of asthma [odds ratio (OR) 11.56, 95% confidence interval (CI) 1.41-255.77, P=0.021], high soil exposure (≥2 hours per week, OR 4.31, 95% CI 1.72-11.45, P<0.01), shower use in a bathroom (OR 4.57, 95% CI 1.28-23.23, P=0.018) and swimming in a pool (OR 9.69, 95% CI 1.21-206.92, P<0.01). Conclusions: Environmental exposure was associated with polyclonal and mixed mycobacterial MAC infection in pulmonary MAC disease.
    Annals of the American Thoracic Society 11/2013; 11(1). DOI:10.1513/AnnalsATS.201309-297OC
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    ABSTRACT: Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. However, pharmacotherapy against the neutrophilic inflammation and emphysema progression associated with exacerbation has not been established. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS)-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms. Mice were exposed to CS and then challenged with polyinosine-polycytidylic acid [poly(I:C)], an agonist for virus-induced innate immunity. Airway neutrophilic inflammation, oxidative stress and lung apoptosis were enhanced in smoke-sensitive C57Bl/6, but not in smoke-resistant NZW mice. Exposure to CS and poly(I:C) challenge accelerated emphysema progression in C57Bl/6 mice. Thioredoxin-1 suppressed neutrophilic inflammation and emphysema progression. Poly(I:C) caused early neutrophilic inflammation through keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor (GM-CSF) release in the lung exposed to CS. Late neutrophilic inflammation was caused by persistent GM-CSF release, which thioredoxin-1 ameliorated. Thioredoxin-1 enhanced pulmonary mRNA expression of MAP kinase phosphatase 1 (MKP-1), and the suppressive effects of thioredoxin-1 on prolonged GM-CSF release and late neutrophilic inflammation disappeared by inhibiting MKP-1. Using a mouse model of COPD exacerbation, we demonstrated that thioredoxin-1 ameliorated neutrophilic inflammation by suppressing GM-CSF release, which prevented emphysema progression. Our findings deepen understanding of the mechanisms underlying the regulation of neutrophilic inflammation by thioredoxin-1 and indicate that thioredoxin-1 could have potential as a drug to counteract COPD exacerbation.
    PLoS ONE 11/2013; 8(11):e79016. DOI:10.1371/journal.pone.0079016 · 3.23 Impact Factor
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    ABSTRACT: (a) To assess the effects of computed tomography (CT) scanners, scanning conditions, airway size, and phantom composition on airway dimension measurement and (b) to investigate the limitations of accurate quantitative assessment of small airways using CT images. An airway phantom, which was constructed using various types of material and with various tube sizes, was scanned using four CT scanner types under different conditions to calculate airway dimensions, luminal area (Ai), and the wall area percentage (WA%). To investigate the limitations of accurate airway dimension measurement, we then developed a second airway phantom with a thinner tube wall, and compared the clinical CT images of healthy subjects with the phantom images scanned using the same CT scanner. The study using clinical CT images was approved by the local ethics committee, and written informed consent was obtained from all subjects. Data were statistically analyzed using one-way ANOVA. Errors noted in airway dimension measurement were greater in the tube of small inner radius made of material with a high CT density and on images reconstructed by body algorithm (p<0.001), and there was some variation in error among CT scanners under different fields of view. Airway wall thickness had the maximum effect on the accuracy of measurements with all CT scanners under all scanning conditions, and the magnitude of errors for WA% and Ai varied depending on wall thickness when airways of <1.0-mm wall thickness were measured. The parameters of airway dimensions measured were affected by airway size, reconstruction algorithm, composition of the airway phantom, and CT scanner types. In dimension measurement of small airways with wall thickness of <1.0 mm, the accuracy of measurement according to quantitative CT parameters can decrease as the walls become thinner.
    PLoS ONE 10/2013; 8(10):e76381. DOI:10.1371/journal.pone.0076381 · 3.23 Impact Factor
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    ABSTRACT: Rationale: Vitamin C (VC) is a potent antioxidant and essential for collagen synthesis. Objectives: We investigated whether VC-treatment prevents and cures smoke-induced emphysema in senescence marker protein-30 knockout (SMP30-KO) mice, which cannot synthesize VC. Methods: Two smoke-exposure experiments using SMP30-KO were conducted. In the first one (a preventive study), four-month-old mice were received minimal VC (0.0375 g/L) [VC(L)] or physiologically sufficient VC (1.5 g/L) [VC(S)], then were exposed to cigarette smoke or smoke-free air for 2 months. Pulmonary evaluations followed when the mice were 6-months of age. The second, study began after the establishment of smoke-induced emphysema (a treatment study). These mice no longer underwent smoke exposure but received VC(S) or VC(L) treatment for 2 months. Morphometric analysis and measurements of oxidative stress, collagen synthesis, and vascular endothelial growth factor (VEGF) in the lungs were evaluated. Measurements and Main Results: Chronic smoke exposure caused emphysema [29.6% increases of mean linear intercepts (MLI) and 106.5% increases of destructive index (DI) compared with the air-only group] in 6-month-old SMP30-KO mice and this emphysema closely resembled human COPD. Furthermore, smoke-induced emphysema persisted in the VC(L) group after smoking cessation, whereas VC-treatment provided pulmonary restoration [18.5% decrease of MLI and 41.3% decrease of DI compared with VC(L) group]. VC-treatment diminished oxidative stress, increased collagen synthesis, and improved VEGF levels in the lungs. Conclusions: Our results suggest that VC not only prevents smoke-induced emphysema in SMP30-KO mice but also restores emphysematous lungs. Therefore, VC may provide a new therapeutic strategy for treating COPD in humans.
    American Journal of Respiratory Cell and Molecular Biology 09/2013; 50(2). DOI:10.1165/rcmb.2013-0121OC · 3.99 Impact Factor

Publication Stats

2k Citations
336.00 Total Impact Points


  • 1993–2015
    • Kyoto University
      • • Department of Respiratory Medicine
      • • Institute for Frontier Medical Sciences
      • • Primate Research Institute
      Kioto, Kyōto, Japan
  • 2013
    • Khon Kaen University
      • Centre for Research and Development of Medical Diagnostic Laboratories
      Kawn Ken, Khon Kaen, Thailand
  • 2010
    • Chiba University
      • Department of Respirology
      Chiba-shi, Chiba-ken, Japan
  • 2006
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 1999
    • McGill University
      Montréal, Quebec, Canada