Kazuhisa Asai

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients

Background Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen.

Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease

PURPOSE Expression of vascular endothelial growth factor (VEGF) is reduced in the lungs of patients with emphysema. We examined whether VEGF levels in sputum differed in patients with emphysema, bronchitis, or asthma, as compared with controls. METHODS Fifty-nine patients with chronic obstructive pulmonary disease (COPD) (25 with emphysema, 19 with chronic bronchitis, and 15 with a mixed type), 20 patients with bronchial asthma, and 11 normal controls were included in the study. The concentration of VEGF in induced sputum and the correlations between VEGF levels and pulmonary function were examined. RESULTS The mean (+/- SD) concentration of VEGF in induced sputum was significantly higher in patients with asthma (6440 +/- 1820 pg/mL, P <0.0001) or bronchitis (4120 +/- 1100 pg/mL, P <0.0001) than in normal controls (1860 +/- 1220 pg/mL), but significantly lower in patients with emphysema (500 +/- 300 pg/mL, P =0.03). The concentration of VEGF in sputum from patients with bronchitis correlated inversely with forced expiratory volume in 1 second (r = -0.87; P =0.0002); in contrast, there was a positive correlation between these two measurements in patients with emphysema (r = 0.82; P <0.0001). In addition, sputum VEGF concentrations correlated with the diffusing capacity of carbon monoxide in patients with emphysema (r = 0.87; P <0.0001), but not in those with bronchitis (r = -0.22; P =0.36). CONCLUSION In patients with bronchitis, increased levels of VEGF in induced sputum were associated with airflow limitation. In contrast, decreased levels of VEGF were associated with airflow limitation and alveolar destruction in patients with emphysema. Thus, our findings suggest that VEGF may affect the pathogenesis of these two common types of COPD.

Increased levels of HMGB-1 and endogenous secretory RAGE in induced sputum from asthmatic patients

BACKGROUND High mobility group box 1 (HMGB-1), a ligand of the receptor for advanced glycation end products (RAGE), is an inflammatory mediator in various disorders. Its endogenous decoy inhibitor, endogenous secretory RAGE (esRAGE), prevents the activation of RAGE signaling, and imbalance between HMGB-1 and esRAGE is known to be a factor determining progression of chronic inflammatory diseases. METHODS We measured HMGB-1 and esRAGE levels in induced sputum from 44 asthmatic patients and 15 normal controls, and examined their correlations with asthma indices including pulmonary function test values and induced sputum indices. RESULTS HMGB-1 levels in induced sputum were significantly higher in asthmatic patients than in normal controls (p < 0.001). Similarly, esRAGE levels were significantly higher in asthmatic patients than in normal controls (p < 0.001). In asthmatic patients, HMGB-1 levels were inversely correlated with percentage of predicted forced expiratory volume in 1 s (%FEV(1)) and FEV(1)/forced vital capacity (FEV(1)/FVC). There was a significant increase in HMGB-1 level associated with severity of asthma (p < 0.001). However, there was no significant increase in esRAGE level associated with severity of asthma. In asthmatic patients, HMGB-1 levels were significantly correlated with percentage of neutrophils in induced sputum. CONCLUSIONS Our findings suggest that the HMGB-1 is a mediator of neutrophilic airway inflammation in asthma and that imbalance between HMGB-1 and esRAGE is related to the severity of asthma. Combined measurement of HMGB-1 and esRAGE may be novel biomarkers in asthma with severe airflow limitation.

Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD

BackgroundSeveral studies have indicated that one of the most potent mediators involved in pulmonary vascular remodeling is vascular endothelial growth factor (VEGF). This study was designed to determine whether airway VEGF level reflects pulmonary vascular remodeling in patients with bronchitis-type of COPD.MethodsVEGF levels in induced sputum were examined in 23 control subjects (12 non-smokers and 11 ex-smokers) and 29 patients with bronchitis-type of COPD. All bronchitis-type patients performed exercise testing with right heart catheterization.ResultsThe mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) after exercise were markedly increased in all bronchitis-type patients. However, both parameters after exercise with breathing of oxygen was significantly lower than in those with breathing of room air. To attenuate the effect of hypoxia-induced pulmonary vasoconstriction during exercise, we used the change in mPAP or PVR during exercise with breathing of oxygen as a parameter of pulmonary vascular remodeling. Change in mPAP was significantly correlated with VEGF level in induced sputum from patients with chronic bronchitis (r = 0.73, p = 0.0001). Moreover, change in PVR was also correlated with VEGF level in those patients (r = 0.57, p = 0.003).ConclusionA close correlation between magnitude of pulmonary hypertension with exercise and VEGF level in bronchitis-type patients could be observed. Therefore, these findings suggest the possibility that VEGF level in induced sputum is a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD.

Validity of HMGB1 measurement in epithelial lining fluid in patients with COPD.

Eur J Clin Invest 2012; 42 (4): 419–426

Phase II study of docetaxel and carboplatin in elderly patients with advanced non-small cell lung cancer.

Background: Mainly single-agent chemotherapy has been considered as standard treatment for elderly patients with non-small cell lung cancer (NSCLC). Docetaxel monotherapy is regarded as a standard treatment for elderly patients with advanced NSCLC, and recent subset analyses have suggested that platinum-based chemotherapy can be safely used in the elderly. This phase II study was conducted to evaluate the efficacy and safety of docetaxel and carboplatin in elderly patients with advanced NSCLC. Methods: Patients enrolled in this study had stage IIIB or IV NSCLC with measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0–2, and were 70 years or older. Treatment consisted of docetaxel at a dose of 60 mg/m2 and carboplatin at area under the curve of 5 mg/ml/min on day 1 every 3 weeks. Results: From October 2003 to April 2006, 30 patients were enrolled. One complete response and 13 partial responses were observed, for an overall response rate of 46.7% (95% confidence interval: 28.8–64.6%). Median progression-free survival and overall survival periods were 4.4 months and 9.9 months, respectively. One-year survival rate was 43.3%. Major grade 3 and 4 hematological toxicities included neutropenia (86.7%), leucopenia (80.0%) and febrile neutropenia (16.7%). Major grade 3 nonhematological toxicities were anorexia (30.0%) and diarrhea (13.3%). There were no grade 4 nonhematological toxicities or treatment-related deaths. Conclusions: Docetaxel combined with carboplatin was an active treatment with manageable toxicity for the treatment of elderly patients with chemotherapy-naive NSCLC.

Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation.

PURPOSE Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. PATIENTS AND METHODS Systemic therapy-naïve patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2-16. This treatment regimen was repeated every 3 weeks until disease progression. RESULTS Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1-35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7-98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9-100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0-21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5-35.5 months). There were no treatment-related deaths. CONCLUSIONS The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.

Increased levels of angiopoietin-2 in induced sputum from smoking asthmatic patients

Background Active cigarette smoking has detrimental effects on asthma morbidity and severity. Angiopoietin‐1 has been shown to protect the microvessels against plasma leakage, whereas angiopoietin‐2 enhances vascular permeability and subsequently induces airway mucosal oedema. Therefore, it is recently thought that angiopoietin‐2 may contribute to the pathophysiology of asthma.

Potential roles of pentosidine in age-related and disease-related impairment of pulmonary functions in patients with asthma

BACKGROUND Pentosidine is well established as an intermolecular cross-linking type of advanced glycation end products, and it accumulates with aging in various connective tissues. OBJECTIVE To determine whether pentosidine contributes to age-related and disease-related impairment of pulmonary functions in patients with asthma. METHODS We measured pentosidine levels in induced sputum from young to elderly patients with asthma and assessed the slope of the nitrogen (N(2)) alveolar plateau (delta N(2)), closing volume (CV), and closing capacity (CC) from a nitrogen washout curve in a single breath. RESULTS Pentosidine levels in induced sputum were significantly higher in patients with asthma than in normal controls (patients with asthma: median, 20.1, interquartile range, 16.7-26.5 ng/mL; normal controls: median, 3.0, interquartile range, 0.7-7.5 ng/mL; P < .001). The levels were closely correlated with age in both normal controls and patients with asthma. However, the slope of age-related increase in pentosidine levels was markedly steeper in patients with asthma than in normal controls. CV/vital capacity, CC/total lung capacity, and delta N(2) increased with aging in both normal controls and patients with asthma. Moreover, in each range of age (21-40, 41-60, 61-80 years), CV/vital capacity, CC/total lung capacity, and delta N(2) were significantly higher in patients with asthma than in normal controls. In addition, pentosidine levels in patients with asthma were closely correlated with each of these variables. CONCLUSION Our results demonstrated the association between sputum levels of pentosidine and age-related small airways function in both normal controls and patients with asthma. Moreover, the age-related increase in pentosidine levels was more pronounced in patients with asthma. These findings will herald new era in the pathophysiology of elderly asthma.

A technological advance comparing epithelial lining fluid from different regions of the lung in smokers.

Cigarette smoking causes inflammatory responses in the airways. However, not all smokers exhibit the development of airflow limitation. This study was designed to determine the implications of small airways inflammation in the development of airflow limitation in smokers by our newly explored method. Twenty-eight smokers (15 smokers without airflow limitation and 13 with airflow limitation) were included in this study. Levels of interleukin-8 (IL-8) and 8-isoprostane were measured in epithelial lining fluid (ELF) from central and peripheral airways separately collected using a bronchoscopic microsampling technique. 8-isoprostane levels in ELF from central or peripheral airways did not significantly differ between the two groups. However, these levels were markedly higher in peripheral than in central airways. Similarly, IL-8 levels in ELF from central airways did not significantly differ between the two groups. In smokers without airflow limitation, IL-8 levels were not higher in peripheral than in central airways. In contrast, in smokers with airflow limitation, IL-8 levels were significantly higher in peripheral airways. Moreover, in smokers with airflow limitation, 8-isoprostane levels in central or peripheral airways were not significantly correlated with FEV(1). However, IL-8 levels in peripheral airways were inversely correlated with FEV(1), though those levels in central airways were not. Thus our technique provides a novel method for ELF sampling from central or peripheral airways separately, and the preliminary evidence that support differences in oxidative stress and neutrophil chemotactic stimulus in these two locations.