Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls

Purpose: To assess the importance of inflammation in chronic obstructive pulmonary disease (COPD) by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups. Patients and methods: This was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures. Results: The overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8), surfactant protein D (SP-D), and Krebs von den Lungen 6 (KL-6) in sputum and clara cell 16 (CC-16), high-sensitivity C-reactive protein (hs-CRP), and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; P＜0.001), neutrophils and MMP-9 (P＜0.001), macrophages and KL-6 (P＜0.01), total cell count and IL-8 (P＜0.05), neutrophils and IL-8 (P＜0.05), and macrophages and MMP-9 (P＜0.05). Significant correlations were also observed between some inflammatory cells in sputum and biomarkers in serum, with the most significant between serum CC-16 and both total cell count (P＜0.005) and neutrophils (P＜0.005) in sputum. Conclusion: These results provide evidence for the first time that COPD in Japanese patients is a multicomponent disease, involving both airway and systemic inflammation, in addition to airway obstruction. Therefore, intervention with anti-inflammatory therapy may provide additional benefit in disease management of COPD in Japan

KL-6 concentration in pulmonary epithelial lining fluid is a useful prognostic indicator in patients with acute respiratory distress syndrome

<p>Abstract</p> <p>Background</p> <p>KL-6 is a mucin-like glycoprotein expressed on the surface of alveolar type II cells. Elevated concentrations of KL-6 in serum and epithelial lining fluid (ELF) in patients with acute respiratory distress syndrome (ARDS) have been previously reported; however, kinetics and prognostic significance of KL-6 have not been extensively studied. This study was conducted to clarify these points in ARDS patients.</p> <p>Methods</p> <p>Thirty-two patients with ARDS who received mechanical ventilation under intubation were studied for 28 days. ELF and blood were obtained from each patient at multiple time points after the diagnosis of ARDS. ELF was collected using a bronchoscopic microsampling procedure, and ELF and serum KL-6 concentrations were measured.</p> <p>Results</p> <p>KL-6 levels in ELF on days 0 to 3 after ARDS diagnosis were significantly higher in nonsurvivors than in survivors, and thereafter, there was no difference in concentrations between the two groups. Serum KL-6 levels did not show statistically significant differences between nonsurvivors and survivors at any time point. When the highest KL-6 levels in ELF and serum sample from each patient were examined, KL-6 levels in both ELF and serum were significantly higher in nonsurvivors than in survivors. The optimal cut-off values were set at 3453 U/mL for ELF and 530 U/mL for serum by receiver operating characteristic (ROC) curve analyses. Patients with KL-6 concentrations in ELF higher than 3453 U/mL or serum concentrations higher than 530 U/mL had significantly lower survival rates up to 90 days after ARDS diagnosis.</p> <p>Conclusions</p> <p>ELF and serum KL-6 concentrations were found to be good indicators of clinical outcome in ARDS patients. Particularly, KL-6 levels in ELF measured during the early period after the diagnosis were useful for predicting prognosis in ARDS patients.</p

Pulmonary alveolar proteinosis after lung transplantation: Two case reports and literature review

Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management

Cross-sectional and prospective study of the association between lung function and prediabetes

Objectives: A growing body of evidence suggests that there is a relationship between impaired lung function and the risk of developing diabetes mellitus (DM). However, it is not known if this reflects a causal effect of lung function on glucose metabolism. To clarify the relationship between lung function and the development of DM, we examined the incidence of newly diagnosed prediabetes (a precursor of DM) among subjects with normal glucose tolerance (NGT) at baseline. Design: Primary analysis of an occupational cohort with both cross-sectional and longitudinal data (follow-up duration mean±SD: 28.4±6.1 months). Setting and participants: Data were analysed from 1058 men in a cross-sectional study and from 560 men with NGT in a longitudinal study. Outcomes and methods: Impaired lung function (per cent predicted value of forced vital capacity (%FVC) or per cent value of forced expiratory volume 1 s/FVC (FEV1/FVC ratio)) in relation to the ratio of prediabetes or DM in a cross-sectional study and development of new prediabetes in a longitudinal study. NGT, prediabetes including impaired glucose tolerance (IGT) and increased fasting glucose (IFG) and DM were diagnosed according to 75 g oral glucose tolerance tests. Measurements and main results: %FVC at baseline, but not FEV1/FVC ratio at baseline, was significantly associated with the incidences of DM and prediabetes. Among prediabetes, IGT but not IFG was associated with %FVC. During follow-up, 102 subjects developed prediabetes among those with NGT. A low %FVC, but not FEV1/FVC ratio, was predictive of an increased risk for development of IGT, but not of IFG. Conclusions: Low lung volume is associated with an increased risk for the development of prediabetes, especially IGT, in Japanese men. Although there is published evidence for an association between chronic obstructive pulmonary disease and DM, prediabetes is not associated with the early stage of COPD.This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 23390222 and 24659405), and a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan

Inhibition of Plasminogen Activator Inhibitor- 1 Attenuates Transforming Growth Factor- β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts

Transforming growth factor-β (TGF-β) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin.We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis

Sputum Vitamin D Binding Protein (VDBP) GC1S/1S Genotype Predicts Airway Obstruction : A Prospective Study in Smokers with COPD

Introduction: The vitamin D binding protein (VDBP, also known as GC-globulin) and vitamin D deficiency have been associated with chronic obstructive pulmonary disease (COPD). rs7041 and rs4588 are two single nucleotide polymorphisms of the VDBP gene, including three common allelic variants (GC1S, GC1F and GC2). Previous studies primarily assessed the serum levels of vitamin D and VDBP in COPD. However, less is known regarding the impact of the local release of VDBP on COPD lung function. Thus, we examined the association of sputum and plasma VDBP with lung function at baseline and at four years, and examined potential genetic polymorphism interactions. Methods: The baseline levels of sputum VDBP, plasma VDBP and plasma 25-OH vitamin D, as well as the GC rs4588 and rs7041 genotypes, were assessed in a 4-year Finnish follow-up cohort (n = 233) of non-smokers, and smokers with and without COPD. The associations between the VDBP levels and the longitudinal decline of lung function were further analysed. Results: High frequencies of the haplotypes in rs7041/rs4588 were homozygous GC1S/1S (42.5%). Higher sputum VDBP levels in stage I and stage II COPD were observed only in carriers with GC1S/1S genotype when compared with non-smokers (p = 0.034 and p = 0.002, respectively). Genotype multivariate regression analysis indicated that the baseline sputum VDBP and FEV1/FVC ratio at baseline independently predicted FEV1% at follow-up. Discussion and Conclusion: The baseline sputum VDBP expression was elevated in smokers with COPD among individuals with the GC1S/1S genotype, and predicted follow-up airway obstruction. Our results suggest that the GC polymorphism should be considered when exploring the potential of VDBP as a biomarker for COPD.Peer reviewe

Reduced endogenous secretory RAGE in blood and bronchoalveolar lavage fluid is associated with poor prognosis in idiopathic pulmonary fibrosis

Background The endogenous secretory receptor for advanced glycation end products (esRAGE) is a soluble isoform produced by alternative splicing of the RAGE gene. The isoform has anti-inflammatory properties due to its inhibition of the RAGE/ligand interaction and is reduced in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the association of esRAGE serum and bronchoalveolar lavage fluid (BALF) levels with progression of IPF. Methods This study included 79 IPF patients and 90 healthy controls. IPF and control serum esRAGE levels were compared, and the correlation between serum and BALF esRAGE levels was analyzed in 57 IPF patient samples. We also investigated the relationship of esRAGE serum and BALF levels with prognoses and lung function parameters in patients with IPF. Results Serum esRAGE levels in IPF patients were significantly lower than those in healthy controls (162.0 +/- 102.4 ng/ml and 200.7 +/- 107.3 ng/ml,p = 0.009), although the baseline characteristics of age and smoking history were not matched. Serum levels of esRAGE were correlated with BALF esRAGE levels (r(s) = 0.317). The BALF esRAGE levels were also correlated with diffusion capacity for carbon monoxide (r(s) = 0.406). A Kaplan-Meier curve analysis and univariate/multivariate Cox hazard proportion analysis revealed that lower levels of esRAGE in blood and BALF were significantly associated with poorer prognoses in patients with IPF. Conclusions Decreased esRAGE levels in BALF and blood were associated with poor prognoses in patients with IPF. These results suggest that esRAGE could be related to the pathophysiology of IPF and serum esRAGE could be a potential prognostic marker of IPF.Peer reviewe