Redox Regulation in Aging Lungs and Therapeutic Implications of Antioxidants in COPD.

Mammals, including humans, are aerobic organisms with a mature respiratory system to intake oxygen as a vital source of cellular energy. Despite the essentiality of reactive oxygen species (ROS) as byproducts of aerobic metabolism for cellular homeostasis, excessive ROS contribute to the development of a wide spectrum of pathological conditions, including chronic lung diseases such as COPD. In particular, epithelial cells in the respiratory system are directly exposed to and challenged by exogenous ROS, including ozone and cigarette smoke, which results in detrimental oxidative stress in the lungs. In addition, the dysfunction of redox regulation due to cellular aging accelerates COPD pathogenesis, such as inflammation, protease anti-protease imbalance and cellular apoptosis. Therefore, various drugs targeting oxidative stress-associated pathways, such as thioredoxin and N-acetylcysteine, have been developed for COPD treatment to precisely regulate the redox system. In this review, we present the current understanding of the roles of redox regulation in the respiratory system and COPD pathogenesis. We address the insufficiency of current COPD treatment as antioxidants and discuss future directions in COPD therapeutics targeting oxidative stress while avoiding side effects such as tumorigenesis.

Effect of repetitive peripheral magnetic stimulation combined with motor imagery on the corticospinal excitability of antagonist muscles.

OBJECTIVE: Repetitive peripheral magnetic stimulation (rPMS) combined with motor imagery facilitates the corticospinal excitability of the agonist muscles. However, the effects of rPMS combined with motor imagery on the corticospinal excitability of the antagonist muscles are unclear. This is an important aspect for applying rPMS in neurorehabilitation for sensorimotor dysfunction. Therefore, we investigated the real-time changes of corticospinal excitability of antagonist muscles during rPMS combined with motor imagery. METHODS: Fourteen healthy volunteers underwent four different experimental conditions: rest, rPMS, motor imagery, and rPMS combined with motor imagery (rPMS + motor imagery). In the rPMS and rPMS + motor imagery conditions, rPMS (25 Hz, 1600 ms/train, 1.5× of the motor threshold) was delivered to the dorsal side of the forearm. In motor imagery and rPMS + motor imagery, the participant imagined wrist extension movements. Transcranial magnetic stimulation was delivered to record motor-evoked potentials of the antagonist muscle during experimental interventions. RESULTS: The motor-evoked potential (normalized by rest condition) values indicated no difference between rPMS, motor imagery, and rPMS + motor imagery. CONCLUSION: These results suggest that rPMS combined with motor imagery has no effect on the corticospinal excitability of the antagonist muscles and highlight the importance of investigating the effects of rPMS combined with motor imagery at the spinal level.

Cigarette smoke reversibly activates hypoxia-inducible factor 1 in a reactive oxygen species-dependent manner.

Cigarette smoke (CS) is a major contributor to the development of a large number of fatal and debilitating disorders. However, the precise molecular mechanisms underlying the effects of CS in lung disease are largely unknown. To elucidate these pathophysiological processes, we examined the in vitro and in vivo effects of CS extract (CSE) and CS on the transcription factor, hypoxia-inducible factor 1 (HIF-1). CSE induced concentration- and time-dependent accumulation of HIF-1α protein in human lung epithelial-like cells under non-hypoxic conditions. Genes upregulated by HIF-1, including vascular endothelial growth factor and regulated in development and DNA damage response 1, both of which are involved in smoking-induced emphysematous changes, were increased by CSE treatment under non-hypoxic conditions in vitro and in vivo. Further investigation revealed that reactive oxygen species were generated in cells exposed to CSE and were required for CSE-mediated induction of HIF-1α protein, as was activation of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. In conclusion, we demonstrated that CSE and CS induced HIF-1 activation in vitro and in vivo, respectively. The evidence warrants further investigation to indicate that HIF-1 plays an important role in CS-induced gene expression, which is deeply involved in pulmonary cellular stress and small airway remodelling.

Association of COPD exacerbation frequency with gene expression of pattern recognition receptors in inflammatory cells in induced sputum.

BACKGROUND: 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. AIMS: This prospective observational study was conducted to detect any association between exacerbation and PRR expression. METHODS: 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. RESULTS: 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. CONCLUSION: TLR3 expression in inflammatory cells might affect the susceptibility to COPD exacerbation.

p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice.

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-1ß, 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.

Thioredoxin-1 protects against neutrophilic inflammation and emphysema progression in a mouse model of chronic obstructive pulmonary disease exacerbation.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

Longitudinal study of spatially heterogeneous emphysema progression in current smokers with chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema. METHODS: We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥ 3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers. RESULTS: D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p=0.008; -0.045 vs. -0.01, p=0.004; 13.9 vs. 1.1, p=0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes. CONCLUSIONS: Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.

Peri-diaphragmatic lung volume assessed by computed tomography correlates with quality of life in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Health-related quality of life (HRQoL) is important in the management of chronic obstructive pulmonary disease (COPD). In patients with emphysema, lung hyperinflation identified radiologically as shortening and flattening of the diaphragm is associated with impaired HRQoL. It remains unclear whether shortening of the diaphragm and/or alteration in chest wall shape are associated with reduced pulmonary function and HRQoL. METHODS: Pulmonary function testing and chest computed tomography (CT) were performed, and the St. George's Respiratory Questionnaire (SGRQ) was administered to 123 patients with COPD. Using CT images, the ratio of volume of lung region adjacent to the diaphragm dome to total lung volume (DLV%) was evaluated as a novel CT index, and conventional indices, including percent low attenuation volume (LAV%), wall area percent (WA%), total lung volume and diaphragm length (Ldi) were calculated. RESULTS: DLV% was significantly correlated with Ldi. DLV% and Ldi were inversely correlated with lung hyperinflation, assessed as the ratio of residual volume to total lung capacity, independent of LAV% and WA%. Unlike Ldi, DLV% was inversely associated with all components and total scores for the SGRQ, independent of the severity of emphysema and airflow limitation. CONCLUSIONS: Reduced lung volume around the diaphragm correlated with lung hyperinflation and HRQoL, independent of emphysema severity. This needs to be verified in additional studies.

Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease.

BACKGROUND: To identify patients with chronic obstructive pulmonary disease (COPD) who are susceptible to frequent exacerbations is important. Although periodontitis aggravated by poor oral hygiene might increase the risk of lower respiratory tract infection, the relationship between periodontitis and COPD exacerbations remains unknown. This prospective cohort study investigates the relationship between periodontitis-related antibody and exacerbation frequency over a one-year period. METHODS: We assessed an IgG antibody titer against Porphyromonas gingivalis, which is a major pathogen of periodontitis, and then prospectively followed up 93 individuals over one year to detect exacerbations. RESULTS: The numbers of exacerbations and the rate of individuals with frequent exacerbations (at least two per year) were significantly lower in patients with higher IgG titer than those with normal IgG titer (0.8 vs. 1.2 per year, p= 0.045 and 14.3 vs. 38.6%, p= 0.009, respectively). Multivariate logistic regression analysis showed that being normal-IgG titer for periodontitis-related antibody significantly increased the risk of frequent exacerbations (relative risk, 5.27, 95% confidence interval, 1.30-25.7; p = 0.019) after adjusting for other possible confounders, such as a history of exacerbations in the past year, disease severity, COPD medication and smoking status. CONCLUSIONS: Normal-IgG titer for periodontitis-related antibody can be an independent predictor of frequent exacerbations. Measuring periodontitis-related antibody titers might be useful to identify patients with susceptibility to frequent exacerbations so that an aggressive prevention strategy can be designed.

Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease.

BACKGROUND: The progression of chronic obstructive pulmonary disease (COPD) considerably varies among patients. Those with emphysema identified by quantitative computed tomography (CT) are associated with the rapid progression assessed by forced expiratory volume in one second (FEV1). However, whether the rate of the decline in lung function is independently affected by the regional distribution or the severity of emphysema in the whole lung is unclear. METHODS: We followed up 131 male patients with COPD for a median of 3.7 years. We measured wall area percent (WA%) in right apical segmental bronchus, total lung volume, percent low attenuation volume (LAV%), and the standard deviation (SD) of LAV% values from CT images of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal emphysema heterogeneity. Annual changes in FEV1 were then determined using a random coefficient model and relative contribution of baseline clinical parameters, pulmonary function, and CT indexes including LAV%, SD-LAV, and WA% to annual changes in FEV1 were examined. RESULTS: The mean (SD) annual change in FEV1 was -44.4 (10.8) mL. Multivariate random coefficient model showed that higher baseline FEV1, higher LAV%, current smoking, and lower SD-LAV independently contributed to an excessive decline in FEV1, whereas ratio of residual volume to total lung capacity, ratio of diffusing capacity to alveolar ventilation, and WA% did not, after adjusting for age, height, weight, and ratio of CT-measured total lung volume to physiologically-measured total lung capacity. CONCLUSIONS: A more homogeneous distribution of emphysema contributed to an accelerated decline in FEV1 independently of baseline pulmonary function, whole-lung emphysema severity, and smoking status. In addition to whole-lung analysis of emphysema, CT assessment of the cranial-caudal distribution of emphysema might be useful for predicting rapid, progressive disease and for developing a targeted strategy with which to prevent disease progression.

Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD.

Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Oxidative stress induced interleukin-32 mRNA expression in human bronchial epithelial cells.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells. METHODS: Human bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors. RESULTS: There were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity. Further, knocking down CREB expression by siRNA resulted in significant suppression of IL-32 induction by IFNγ and H2O2 in HBE cells. CONCLUSION: IL-32 expression in airway epithelium may be augmented by inflammation and oxidative stress, which may occur in COPD acute exacerbation. c-Jun and CREB are key transcriptional factors in IFNγ and H2O2 induced IL-32 expression.

Impact of COPD exacerbations on osteoporosis assessed by chest CT scan.

BACKGROUND: COPD pathology involves not only the lungs but also extrapulmonary abnormalities. Osteoporosis is one of the most important abnormalities because it may cause vertebral compression fractures and deteriorate pulmonary function. COPD patients have many risk factors for osteoporosis, such as low BMI, decreased activity, systemic inflammation, and use of corticosteroids. Some of these factors have been shown to deteriorate with COPD exacerbations. We previously demonstrated the correlation between emphysema and osteoporosis and between emphysema progression and COPD exacerbations. Thus, the hypothesis that exacerbation causes osteoporosis progression in COPD patients was investigated. METHODS: Forty-two COPD patients not on osteoporosis treatment for over 2 years were recruited. During follow-up, exacerbations had been prospectively recorded. Thoracic vertebral bone mineral density (BMD) was measured using chest CT, and the annual change in BMD was calculated. The change was compared between patients with and without a history of exacerbations. RESULTS: The decrease in thoracic vertebral BMD was greater in patients with than in those without a history of exacerbations (median ΔBMD mg/ml·year: -3.78 versus -0.30, p = 0.02). Moreover, multivariate regression analysis showed that exacerbations and baseline PaO2 were independent predictors of the BMD decrease (R² = 0.20, p = 0.007, and R² = 0.09, p = 0.03, respectively) after adjustment for baseline age, smoking status, and airflow limitation. CONCLUSIONS: This is the first longitudinal study to demonstrate that COPD exacerbations are independently associated with osteoporosis progression. Osteoporosis progression should be evaluated in COPD patients, especially in those with a history of frequent exacerbations.

A NOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population.

BACKGROUND AND OBJECTIVE: Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide-binding and oligomerization domain (NOD)1 and NOD2 genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed. METHODS: Japanese COPD patients (n = 228) and non-COPD smokers (n = 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs of NOD1 and 5 tag SNPs of NOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro-inflammatory cytokines. RESULTS: The distribution of NOD2 rs1077861 genotypes differed between Japanese COPD patients and non-COPD smokers (P = 0.036). This SNP was also associated with a lower FEV(1) % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA, P = 0.03) and DL(CO) /V(A) (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA, P = 0.036) in COPD patients. NOD2 gene expression after stimulation with 10 ng/mL of tumour necrosis factor-α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils (P = 0.015). CONCLUSIONS: The NOD2 rs1077861 SNP may influence the development and progression of COPD in Japanese subjects.

[Novel therapeutics for COPD].

Chronic obstructive pulmonary disease (COPD) is a progressing lung disorder mainly caused by cigarette smoking. The central pathogeneses are inflammation, oxidative stress, apoptosis and excessive proteases which lead to matrix degradation and loss of lung cells. The inflammation is somehow perpetuated even after quit smoking and is generally refractory to glucocorticoid therapy. It is thus hoped to develop novel anti-inflammatory agents for prevention of disease progression. As molecular mechanisms of COPD are gradually clarified, numerous numbers of molecular targeted agents have been developed for therapeutics. In this section, novel agents for COPD targeted at signal transduction molecules, cytokines, chemokines and those receptors, adhesion molecules, oxidative stress and proteases are discussed.

Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease.

RATIONALE: Low-attenuation areas assessed by computed tomography reflect the extent of pathological emphysema and correlate with airflow limitation and mortality in patients with chronic obstructive pulmonary disease. The cumulative size distribution of low-attenuation area clusters follows a power law characterized by an exponent, D. The values of D reflect the complexity of the terminal airspace geometry and sensitively detect alveolar structural changes. Exacerbations of chronic obstructive pulmonary disease have a negative impact on lung function and prognosis. However, the impact on emphysema progression remains unclear. OBJECTIVES: We investigated the relationship between exacerbation and emphysema progression assessed by computed tomography in patients with chronic obstructive pulmonary disease. METHODS: Exacerbations were prospectively recorded for 2 years. Annual changes in computed tomography parameters of emphysema were compared between patients with and without a history of exacerbations. MEASUREMENTS AND MAIN RESULTS: In patients with exacerbations, increases in the percentage of low-attenuation areas and decreases in D were greater than in patients without exacerbations. To interpret these results, we established a novel simulation model and found that not only enlargement of preexisting low-attenuation areas but also coalescence of adjoining low-attenuation areas due to alveolar wall destruction caused emphysema progression in patients with exacerbations. CONCLUSIONS: This is the first longitudinal study to demonstrate that exacerbations are involved in emphysema progression in patients with chronic obstructive pulmonary disease. Emphysema progression should be evaluated as part of the outcomes of exacerbations in the management of chronic obstructive pulmonary disease.

CT scan findings of emphysema predict mortality in COPD.

BACKGROUND: Emphysematous change as assessed by CT imaging has been reported to correlate with COPD prognostic factors such as FEV(1) and diffusing capacity of the lung for carbon monoxide (Dlco). However, few studies have assessed the relationship between CT scan assessment and COPD mortality from mild to severe stages of the disease. In this study, we analyzed this relationship in patients with various stages of COPD. METHODS: Two hundred and fifty-one outpatients with stable COPD were included in the study. CT scan and pulmonary function tests were performed at study entry in a single institution. The percentage of low attenuation area was measured to quantitatively evaluate emphysematous change with a custom-made software. Prognostic data also were collected, and the median follow-up time was 8 years. RESULTS: Of the 251 patients, 79 died, with 40 classified as respiratory deaths not involving lung cancer. Univariate Cox analysis revealed that emphysematous change as assessed by CT scan, lung function, age, or BMI were significantly correlated with mortality. Multivariate analysis revealed that emphysematous change as assessed by CT scan had the best association with mortality. CONCLUSIONS: Emphysematous change as assessed by CT scan predicts respiratory mortality in outpatients with various stages of COPD.

Lipopolysaccharide induced connective tissue growth factor gene expression in human bronchial epithelial cells.

BACKGROUND AND OBJECTIVE: Connective tissue growth factor (CTGF) is up-regulated in the lungs of patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke and repeated bacterial infections, both of which are rich sources of LPS, are major causes of COPD. The high levels of LPS in lung epithelial lining fluid also suggest that it may have a considerable impact on the airway epithelium, in terms of cytokine and growth factor production. The aim of this study was to clarify the mechanism of LPS-induced CTGF expression in bronchial epithelial cells. METHODS: The expression and transcriptional regulation of the CTGF gene were assessed using the cultured human bronchial epithelial cell line, BEAS-2B. RESULTS: LPS significantly up-regulated CTGF mRNA expression in a dose-dependent fashion, with 100 microg/mL LPS causing a twofold increase after 2 h. CTGF protein expression was also up-regulated by LPS after 8 h. Transforming growth factor-beta1 mRNA expression was not changed by LPS treatment. A pharmacological inhibitor of nuclear factor (NF)-kappaB, MG132, inhibited LPS-induced CTGF mRNA expression. Furthermore, luciferase assays demonstrated that deletion of base pairs -253 to -53 from the CTGF promoter, where the Smad and proximal NF-kappaB binding sites are located, decreased the induction of CTGF by LPS. After stimulation with LPS, the p65 subunit of NF-kappaB was shown to be bound to the CTGF promoter in vitro and in situ. CONCLUSIONS: LPS directly induced CTGF expression in bronchial epithelial cells, independently of transforming growth factor-beta1, suggesting a possible mechanism for airway remodelling in COPD that is induced by smoking and repeated bacterial infections.

Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study.

BACKGROUND: Health status, dyspnea and psychological status are important clinical outcomes in chronic obstructive pulmonary disease (COPD). However, forced expiratory volume in one second (FEV1) measured by spirometry, the standard measurement of airflow limitation, has only a weak relationship with these outcomes in COPD. Recently, in addition to spirometry, impulse oscillometry (IOS) measuring lung resistance (R) and reactance (X) is increasingly being used to assess pulmonary functional impairment. METHODS: We aimed to identify relationships between IOS measurements and patient-reported outcomes in 65 outpatients with stable COPD. We performed pulmonary function testing, IOS, high-resolution computed tomography (CT), and assessment of health status using the St. George's Respiratory Questionnaire (SGRQ), dyspnea using the Medical Research Council (MRC) scale and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then investigated the relationships between these parameters. For the IOS measurements, we used lung resistance at 5 and 20 Hz (R5 and R20, respectively) and reactance at 5 Hz (X5). Because R5 and R20 are regarded as reflecting total and proximal airway resistance, respectively, the fall in resistance from R5 to R20 (R5-R20) was used as a surrogate for the resistance of peripheral airways. X5 was also considered to represent peripheral airway abnormalities. RESULTS: R5-R20 and X5 were significantly correlated with the SGRQ and the MRC. These correlation coefficients were greater than when using other objective measurements of pulmonary function, R20 on the IOS and CT instead of R5-R20 and X5. Multiple regression analyses showed that R5-R20 or X5 most significantly accounted for the SGRQ and MRC scores. CONCLUSIONS: IOS measurements, especially indices of peripheral airway function, are significantly correlated with health status and dyspnea in patients with COPD. Therefore, in addition to its simplicity and non-invasiveness, IOS may be a useful clinical tool not only for detecting pulmonary functional impairment, but also to some extent at least estimating the patient's quality of daily life and well-being.

Abnormal swallowing reflex and COPD exacerbations.

BACKGROUND: It is unclear whether an abnormal swallowing reflex affects COPD exacerbations. This study investigated the prevalence of abnormal swallowing reflexes and its relationship with COPD exacerbation prospectively. We also clarified its association with gastroesophageal reflux disease (GERD) and airway bacterial colonization. METHODS: Swallowing reflex and serum C-reactive protein (CRP) levels were examined in subjects with stable COPD and in control subjects. Concurrently, GERD symptoms were assessed using a self-reported questionnaire, and sputum bacterial cultures were investigated in the same subjects. Exacerbations were counted prospectively during the following 12 months. RESULTS: The study group comprised 67 subjects with COPD and 19 controls. The prevalence of abnormal swallowing reflex was significantly higher in subjects with COPD (22/67) than controls (1/19; P = .02). Among subjects with COPD, the serum CRP level, GERD symptoms, isolation of sputum bacteria, and the frequency of exacerbations were significantly increased in those with abnormal swallowing reflexes compared with controls (2.72 vs 1.04 mg/L, P = .04, for serum CRP level; 6.75 vs 4.10 points, P = .04, for GERD symptoms; 5/11 vs 3/22, P = .04, for the isolation of sputum bacteria; and 2.82 vs 1.56/y, P = .007, for the annual frequency of exacerbations). Multivariable analysis confirmed that abnormal swallowing reflex was significantly associated with frequent exacerbations (>or= 3/y; P = 0.01). CONCLUSIONS: Abnormal swallowing reflexes frequently occurred in subjects with COPD and predisposed them to exacerbations. Abnormal swallowing reflexes in COPD might be affected by the comorbidity of GERD, and cause bacterial colonization.