Yoshiaki Kitaguchi

Clinical characteristics of combined pulmonary fibrosis and emphysema

Background and objective:  Patients with combined pulmonary fibrosis and emphysema (CPFE) are sometimes seen, and we speculate that these patients have some different clinical characteristics from COPD patients. This study clarifies the clinical characteristics of CPFE patients.

Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography

Objective and background:  The present study was performed to clarify the clinical characteristics of patients with COPD classified into phenotypes according to the dominancy of emphysema and the presence of bronchial wall thickening (BWT) evaluated by chest high‐resolution CT.

Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma

Background Chronic obstructive pulmonary disease (COPD) and asthma may overlap and converge in older people (overlap syndrome). It was hypothesized that patients with overlap syndrome may have different clinical characteristics such as sputum eosinophilia, and better responsiveness to treatment with inhaled corticosteroid (ICS). Methods Sixty-three patients with stable COPD (forced expiratory volume in 1 second [FEV1] ≤80%) underwent pulmonary function tests, including reversibility of airflow limitation, arterial blood gas analysis, analysis of inflammatory cells in induced sputum, and chest high-resolution computed tomography. The inclusion criteria for COPD patients with asthmatic symptoms included having asthmatic symptoms such as episodic breathlessness, wheezing, cough, and chest tightness worsening at night or in the early morning (COPD with asthma group). The clinical features of COPD patients with asthmatic symptoms were compared with those of COPD patients without asthmatic symptoms (COPD without asthma group). Results The increases in FEV1 in response to treatment with ICS were significantly higher in the COPD with asthma group. The peripheral eosinophil counts and sputum eosinophil counts were significantly higher. The prevalence of patients with bronchial wall thickening on chest high-resolution computed tomography was significantly higher. A significant correlation was observed between the increases in FEV1 in response to treatment with ICS and sputum eosinophil counts, and between the increases in FEV1 in response to treatment with ICS and the grade of bronchial wall thickening. Receiver operating characteristic curve analysis revealed 82.4% sensitivity and 84.8% specificity of sputum eosinophil count for detecting COPD with asthma, using 2.5% as the cutoff value. Conclusion COPD patients with asthmatic symptoms had some clinical features. ICS should be considered earlier as a potential treatment in such patients. High sputum eosinophil counts and bronchial wall thickening on chest high-resolution computed tomography might therefore be a good predictor of response to ICS.

Acrolein Induces Endoplasmic Reticulum Stress and Causes Airspace Enlargement

Background Given the relative abundance and toxic potential of acrolein in inhaled cigarette smoke, it is surprising how little is known about the pulmonary and systemic effects of acrolein. Here we test the hypothesis whether systemic administration of acrolein could cause endoplasmic reticulum (ER) stress, and lung cell apoptosis, leading to the enlargement of the alveolar air spaces in rats. Methods Acute and chronic effects of intraperitoneally administered acrolein were tested. Mean alveolar airspace area was measured by using light microscopy and imaging system software. TUNEL staining and immunohistochemistry (IHC) for active caspase 3 and Western blot analysis for active caspase 3, and caspase 12 were performed to detect apoptosis. The ER-stress related gene expression in the lungs was determined by Quantitative real-time PCR analysis. Acrolein-protein adducts in the lung tissue were detected by IHC. Results Acute administration of acrolein caused a significant elevation of activated caspase 3, upregulation of VEGF expression and induced ER stress proteins in the lung tissue. The chronic administration of acrolein in rats led to emphysematous lung tissue remodeling. TUNEL staining and IHC for cleaved caspase 3 showed a large number of apoptotic septal cells in the acrolein-treated rat lungs. Chronic acrolein administration cause the endoplasmic reticulum stress response manifested by significant upregulation of ATF4, CHOP and GADd34 expression. In smokers with COPD there was a considerable accumulation of acrolein-protein adducts in the inflammatory, airway and vascular cells. Conclusions Systemic administration of acrolein causes endoplasmic reticulum stress response, lung cell apoptosis, and chronic administration leads to the enlargement of the alveolar air spaces and emphysema in rats. The substantial accumulation of acrolein-protein adducts in the lungs of COPD patients suggest a role of acrolein in the pathogenesis of emphysema.

Effects of bronchodilators on dynamic hyperinflation following hyperventilation in patients with COPD

Background and objective:  The present study was performed to examine the occurrence of dynamic hyperinflation following hyperventilation in COPD patients and former smokers without COPD, and the efficacy of short‐acting anticholinergic agents (SAAC) and β2‐agonists (SABA) for lung hyperinflation following metronome‐paced hyperventilation in COPD.

Carbocisteine Protects Against Emphysema Induced by Cigarette Smoke Extract in Rats

BACKGROUND Chronic inflammation, imbalance of proteolytic and antiproteolytic activities, oxidative stress, and apoptosis of lung structural cells contribute to the pathogenesis of COPD. There is increasing evidence that carboxymethylcysteine (also known as carbocisteine) (CMC), which is commonly used for its mucoactive property, has diverse pharmacologic actions, including significant antioxidant activity. We hypothesize that CMC protects against cigarette smoke extract (CSE)-induced emphysema in rats via its antioxidant action. METHODS Sprague-Dawley rats were divided into four groups (n = 6 in each group): control group, CSE group, CSE + 125 mg/kg/d of CMC group, and CSE + 250 mg/kg/d of CMC group. The CSE was injected intraperitoneally once a week for 3 weeks, and CMC was administered daily via a gastric gavage for the same duration. Antioxidant activity in the pulmonary and serum levels, apoptotic index, caspase-3 activity, and matrix metalloproteinase (MMP)-2 and MMP-9 activities in lung tissues were measured. RESULTS CMC significantly protected against alveolar enlargement and parenchymal destruction in rats injected with CSE, resulting in prevention of the development of CSE-induced emphysema in the rats. CMC significantly protected the antioxidant activity in both the pulmonary and systemic levels, reduced pathologic apoptosis, and inhibited MMP-2 and MMP-9 activities in the lungs of rats with CSE-induced emphysema. CONCLUSIONS CMC protected against the development of CSE-induced emphysema in rats. The molecular mechanisms that were involved with stabilizing the biologic antioxidant activity resulted from the administration of CMC, which was connected to the inhibition of apoptosis and the reversal of the imbalance of proteolytic and antiproteolytic enzyme activities, eventually achieving the protection of the alveolar architecture of rats with emphysema.

Annual changes in pulmonary function in combined pulmonary fibrosis and emphysema: Over a 5-year follow-up

BACKGROUND Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder that has been previously described, and the distinct features of CPFE in comparison with chronic obstructive pulmonary disease (COPD) have been reported. However, the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients have not yet been reported. METHODS We retrospectively enrolled patients with CPFE and COPD who had undergone pulmonary function tests more than five times during a follow-up period of more than five years. The baseline clinical characteristics and the annual changes in pulmonary function during the follow-up period in 16 stable CPFE patients were compared with those in 19 stable COPD patients. Annual changes in pulmonary function were estimated from linear regressions, with assumptions for time-dependency and linearity. We analyzed the time-dependent fluctuations in pulmonary function for the two disorders. RESULTS Annual decreases in VC and FVC in the CPFE group were significantly higher than those in the COPD group. Annual decrease in FEV1/FVC in the COPD group was significantly higher than in the CPFE group. During the follow-up period, FEV1/FVC in the CPFE group appeared to improve because of annual decrease in FVC. Annual decreases in DLco and DLco/VA in the CPFE group were significantly higher than those in the COPD group. CONCLUSION This is the first report showing the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients during a follow-up period of more than five years. This study revealed that the physiologic consequences of CPFE including the rate of progression of pulmonary function impairment were different from those of COPD.

Pulmonary function impairment in patients with combined pulmonary fibrosis and emphysema with and without airflow obstruction.

Background The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is a recently described entity associating upper-lobe emphysema and lower-lobe fibrosis. We sought to evaluate differences in pulmonary function between CPFE patients with and without airflow obstruction. Subjects and methods Thirty-one CPFE patients were divided into two groups according to the presence or absence of irreversible airflow obstruction based on spirometry (forced expiratory volume in 1 second/forced vital capacity <70% following inhalation of a β2-agonist) as follows: CPFE patients with airflow obstruction (CPFE OB+ group, n=11), and CPFE patients without airflow obstruction (CPFE OB− group, n=20). Pulmonary function, including respiratory impedance evaluated using impulse oscillometry and dynamic hyperinflation following metronome-paced incremental hyperventilation, was retrospectively analyzed in comparison with that observed in 49 chronic obstructive pulmonary disease (COPD) patients (n=49). Results In imaging findings, low-attenuation-area scores on chest high-resolution computed tomography, representing the degree of emphysema, were significantly lower in the CPFE OB− group than in the CPFE OB+ and COPD groups. In contrast, the severity of pulmonary fibrosis was greater in the CPFE OB− group than in the CPFE OB+ group. In pulmonary function, lung hyperinflation was not apparent in the CPFE OB− group. Impairment of diffusion capacity was severe in both the CPFE OB− and CPFE OB+ groups. Impulse oscillometry showed that respiratory resistance was not apparent in the CPFE OB− group compared with the COPD group, and that easy collapsibility of small airways during expiration of tidal breath was not apparent in the CPFE OB+ group compared with the COPD group. Dynamic hyperinflation following metronome-paced incremental hyperventilation was significantly greater in the COPD group than in the CPFE OB− group, and also tended to be greater in the CPFE OB+ group than in the CPFE OB− group. Conclusion The mechanisms underlying impairment of physiological function may differ among CPFE OB+ patients, CPFE OB− patients, and COPD patients. CPFE is a heterogeneous disease, and may have distinct phenotypes physiologically and radiologically.

Hydrogen Peroxide Content and pH of Expired Breath Condensate from Patients with Asthma and COPD

Abstract Background: Oxidative stress is implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Analysis of the expired breath condensate (EBC) has been suggested to provide non-invasive inflammatory markers that reflect oxidative stress in the airways. Objective: The present study attempts to elucidate whether the hydrogen peroxide (H2O2) levels and pH values in EBC may be useful as biomarkers of the activity or severity of asthma and COPD. Methods: We measured the H2O2 levels and pH values using a derivatives of reactive oxygen metabolites exhalation test kit (Diacron) and a pH analyser, respectively, in EBC obtained using an EcoScreen from 29 patients with asthma, 33 with COPD, and 33 healthy individuals (all non-smokers). We then examined the relationships among oxidative stress and the asthma control test (ACT) or COPD assessment test (CAT) scores, pulmonary function, fractional exhaled nitric oxide (FeNO), and the extent of low attenuation areas on HRCT. Results: The H2O2 levels were elevated and pH was lower in both asthma (H2O2; 8.75 ± 0.88 μM, p < 0.01, pH; 7.14 ± 0.07, p < 0.05) and COPD (H2O2; 7.44 ± 0.89 μM, p < 0.01, pH; 6.87 ± 0.10, p < 0.01) compared with control subjects (H2O2; 3.42 ± 0.66 μM, pH; 7.35 ± 0.04). Neither the H2O2 levels nor pH correlated with the ACT scores and FeNO in asthma patients. Neither the H2O2 levels nor pH significantly correlated with the pulmonary function in asthma and COPD. However, the CAT scores significantly correlated with the H2O2 levels in patients with COPD (r = 0.52, p < 0.01). Conclusions: These findings suggest that oxidative stress is involved in the pathogenesis of asthma and COPD and that the H2O2 levels in EBC might reflect the health status in COPD.

The association of Toll-like receptor 4 gene polymorphisms with the development of emphysema in Japanese subjects: a case control study

BackgroundThe principal role of Toll-like receptor 4 (TLR4) is the induction of immune responses to lipopolysaccharides. Previously, mice deficient in the TLR4 gene exhibited up-regulation of the NADPH oxidase system in the lungs. This resulted in increased oxidant generation and elastolytic activity, which led to pulmonary emphysema. It was suggested that TLR4 might maintain constitutive lung integrity by modulating oxidant generation. We investigated whether single nucleotide polymorphisms (SNPs) in the TLR4 gene were associated with the emphysema phenotype in Japanese subjects with chronic obstructive pulmonary disease (COPD).ResultsSeven SNPs in the TLR4 gene (rs10759930, rs1927914, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped with allelic discrimination assays. The frequencies of SNPs were compared between 106 patients with the emphysema phenotype of COPD and 137 healthy smokers. We found that the positivity of the individuals with the major G allele of rs11536889 was significantly less in the emphysema group than the control group (p = 0.019). The frequencies of the minor C allele and the distribution of the CC genotype as well as the frequency of the major haplotype that carried the minor C allele of rs11536889 were all significantly higher in the emphysema group than the control group (p = 0.0083, 0.019, and 0.004, respectively). Furthermore, the strength of the association of the CC genotype with the emphysema phenotype was in an odds ratio of 2.60 with 95% confidence intervals from 1.17 to 5.78. However, these significances were not apparent after adjust for age and smoking history by logistic regression. No associations were observed between the rs11536889 and the low attenuation area score, the forced expiratory volume, and the carbon monoxide diffusion capacity in the emphysema group.ConclusionsThe minor C allele of the rs11536889 SNP in the TLR4 gene is likely associated with the risk of developing emphysema in the Japanese population.