[Show abstract][Hide abstract] 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.
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.
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.
MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF.
Full-text · Article · Sep 2016 · Respiratory Research
[Show abstract][Hide abstract] ABSTRACT: Background: Alpha1-antitrypsin (ΑAT) deficiency (AATD), a condition of little or no AAT in the serum, is believed to be extremely rare in Japan. However, no such nationwide epidemiological survey has been conducted. The Respiratory Research Failure Group and Japanese Respiratory Society (JRS) cooperated to conduct this survey. Methods: The survey questionnaire was sent by post to 1598 hospitals that have 200 or more beds (excluding mental hospitals), and by e-mail to members of the JRS. Hospitals failing to respond were followed-up by phone. Results: 1467 hospitals replied [response rate=91.8% (1467/1598)], and 114 members responded. Of the 14 probands registered from 10 hospitals and one local practitioner, 9 had severe and 5 had mild AATD. Eleven of these patients were diagnosed with COPD, 1 with COPD and bronchiectasis, 1 with pulmonary emphysema without airflow obstruction, and the remaining 1 with bronchiectasis without airflow obstruction. Mutation analysis of the SERPINA1 gene was performed in 7 patients, 6 of whom (85.7%) had homozygous PI*S iiyama. The prevalence of AATD in Japan was thus estimated to be 24 patients, with a 95% confidence interval (22, 27). When asked if they would prescribe AAT augmentation therapy, 6 of the 10 (60.0%) of respondent attending physicians answered affirmatively if health insurance would cover the treatment. Conclusions: This nationwide survey confirmed that AATD is extremely rare in Japan. Six of 10 care-giving physicians would offer AAT augmentation therapy if the therapy were covered by health insurance in Japan.
No preview · Article · Jan 2016 · Respiratory Investigation
[Show abstract][Hide abstract] ABSTRACT: Background:
Lung perfusions after single lung transplantation (SLT) have not been fully clarified in patients with interstitial lung disease (ILD). The present study aimed to investigate temporal changes in native lung perfusion and their associated clinical factors in patients with ILD who have undergone SLT.
Eleven patients were enrolled. Perfusion scintigraphy was serially performed up to 12 months after SLT. Correlations between the postoperative perfusion ratio in the native lung and clinical parameters, including preoperative perfusion ratio and computed tomography (CT) volumetric parameters, were evaluated.
On average, the perfusion ratio of the native lung was maintained at approximately 30% until 12 months after SLT. However, the ratio declined more significantly in idiopathic pulmonary fibrosis (IPF) than in other ILDs (p = 0.014). The perfusion ratio before SLT was significantly correlated with that at 3 months after SLT (ρ = 0.64, p = 0.048). The temporal change of the perfusion ratio in the native lung did not correlate with those of the CT parameters.
The preoperative perfusion ratio may predict the postoperative perfusion ratio of the native lung shortly after SLT in ILD. Perfusion of the native lung may decline faster in IPF compared with other ILDs. This article is protected by copyright. All rights reserved.
No preview · Article · Jan 2016 · Clinical Transplantation
[Show abstract][Hide abstract] ABSTRACT: Background:
Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported.
In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network.
Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053).
Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.
[Show abstract][Hide abstract] ABSTRACT: We conducted hospital-based contact investigations of 55 serial sputum smear-positive tuberculosis (TB) patients and 771 health care workers (HCWs) from 2006-2013. HCWs who made contact with TB patients in the absence of appropriate airborne precautions were evaluated using interferon gamma release assays to identify TB infection. Twenty-nine HCWs (3.8%) were newly diagnosed with TB infection. The 10 TB patients responsible for transmission had a duration of contact of >7 days by multivariate analysis.
No preview · Article · Jan 2016 · American journal of infection control
[Show abstract][Hide abstract] ABSTRACT: Multi-ciliated airway cells (MCACs) play a role in mucociliary clearance of the lung. However, the efficient induction of functional MCACs from human pluripotent stem cells has not yet been reported. Using carboxypeptidase M (CPM) as a surface marker of NKX2-1(+)-ventralized anterior foregut endoderm cells (VAFECs), we report a three-dimensional differentiation protocol for generating proximal airway epithelial progenitor cell spheroids from CPM(+) VAFECs. These spheroids could be induced to generate MCACs and other airway lineage cells without alveolar epithelial cells. Furthermore, the directed induction of MCACs and of pulmonary neuroendocrine lineage cells was promoted by adding DAPT, a Notch pathway inhibitor. The induced MCACs demonstrated motile cilia with a "9 + 2" microtubule arrangement and dynein arms capable of beating and generating flow for mucociliary transport. This method is expected to be useful for future studies on human airway disease modeling and regenerative medicine.
Full-text · Article · Jan 2016 · Stem Cell Reports
[Show abstract][Hide abstract] ABSTRACT: The relationship between chronic inflammation and cancer is well known. The inflammation increases the permeability of blood vessels and consequently elevates pressure in the interstitial tissues. However, there have been only a few reports on the effects of hydrostatic pressure on cultured cells, and the relationship between elevated hydrostatic pressure and cell properties related to malignant tumors is less well understood. Therefore, we investigated the effects of hydrostatic pressure on the cultured epithelial cells seeded on permeable filters. Surprisingly, hydrostatic pressure from basal to apical side induced epithelial stratification in Madin-Darby canine kidney (MDCK) I and Caco-2 cells, and cavities with microvilli and tight junctions around their surfaces were formed within the multi-layered epithelia. The hydrostatic pressure gradient also promoted cell proliferation, suppressed cell apoptosis, and increased transepithelial ion permeability. The inhibition of protein kinase A (PKA) promoted epithelial stratification by the hydrostatic pressure whereas the activation of PKA led to suppressed epithelial stratification. These results indicate the role of the hydrostatic pressure gradient in the regulation of various epithelial cell functions. The findings in this study may provide clues for the development of a novel strategy for the treatment of the carcinoma.
[Show abstract][Hide abstract] ABSTRACT: Rationale:
The loss of skeletal muscle mass and physical inactivity are important manifestations of chronic obstructive pulmonary disease (COPD), and both are closely related to poor prognoses in patients with COPD. Antigravity muscles are involved in maintaining normal posture and are prone to atrophy due to inactivity. The erector spinae muscle (ESM) group is one of the antigravity muscles and can be assessed via chest computed tomography (CT).
We hypothesized that the cross-sectional area of ESM (ESMCSA) in chest CT images may serve as a predictor of mortality in patients with COPD.
This study was a part of the prospective observational study undertaken at Kyoto University Hospital. ESMCSA was measured in a single axial CT image at the level of the twelfth thoracic vertebrae in patients with COPD. The cross-sectional area of the pectoralis muscles (PMCSA) was also measured. And then we evaluated the relationship between ESMCSA and clinical parameters in patients with COPD including mortality. Age- and height-matched smoking control subjects were also evaluated.
Measurements and main results:
In total, 130 male patients and twenty smoking control males were enrolled in this study. ESMCSA was significantly lower in patients with COPD than in the smoking control subjects and was significantly correlated with disease severity. There was a significant but only moderate correlation between ESMCSA and PMCSA. ESMCSA was significantly correlated with previously reported prognostic factors, such as body mass index (BMI), dyspnea (mMRC), %FEV1, inspiratory-to-total lung capacity ratio (IC/TLC), and emphysema severity (LAA%). Compared to PMCSA, ESMCSA was more strongly associated with mortality in patients with COPD. Among these known prognostic factors, the stepwise multivariate Cox proportional hazards analysis revealed that ESMCSA was the strongest risk factor for mortality (Hazard Ratio (HR), 0.85; 95% confidence interval (CI), 0.79-0.92; p<0.001) and mMRC was an additional factor (HR, 2.35; 95% CI, 1.51-3.65; p<0.001).
ESMCSA assessed via chest CT may be a valuable clinical parameter, as ESACSA correlates significantly with physiological parameters, symptoms and disease prognosis.
No preview · Article · Dec 2015 · Annals of the American Thoracic Society
[Show abstract][Hide abstract] 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.
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.
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.
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.
Full-text · Article · Sep 2015 · Respiratory medicine
[Show abstract][Hide abstract] 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.
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.
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).
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.
Preview · Article · Jul 2015 · BMC Pulmonary Medicine
[Show abstract][Hide abstract] 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 http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] 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.
No preview · Article · Jan 2015 · Journal of Infection and Chemotherapy
[Show abstract][Hide abstract] 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.
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).
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.
TLG correlated significantly with the serum sIL-2R level and may be useful for disease monitoring in IgG4-RD.
Full-text · Article · Dec 2014 · Modern Rheumatology
[Show abstract][Hide abstract] 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.
We recruited 72 patients with pulmonary MAC disease (male [female], 18 ; 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.
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).
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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Jul 2014 · The Journal of Physiological Sciences