Response biomarkers of inhalation exposure to cigarette smoke in the mouse lung.

Cigarette smoking is known to increase the risk of cancer and chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of short-term nose-only inhalation exposure to cigarette smoke in mice. Male 10-week-old C57BL mice were exposed to clean air (control) or mainstream cigarette smoke for 1 h/day, 5 days/week, for 2 or 4 weeks. Exposure to cigarette smoke increased the number of inflammatory cells, especially neutrophils, in the bronchoalveolar lavage fluid, increased inflammatory cell infiltration foci, and caused an increase in the thickness of the peripheral bronchial epithelium. Microarray gene expression analysis indicated that smoke exposure induced inflammatory responses, including leukocyte migration and activation of phagocytes and myeloid cells, as early as two weeks after the initiation of exposure. Importantly, chemokine (C-C motif) ligand 17, resistin-like alpha, and lipocalin 2 were upregulated and may serve as useful markers of the toxic effects of exposure to cigarette smoke before pulmonary histological changes become evident.

Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice.

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.

Obesity and hiatal hernia may be non-allergic risk factors for esophageal eosinophilia in Japanese adults.

BACKGROUND: Esophageal eosinophilia (EE) is a basal condition of eosinophilic esophageal disorders including eosinophilic esophagitis (EoE) and asymptomatic EE. EoE is considered as an allergic disorder, while it is unclear whether other non-allergic conditions are involved in the pathophysiology of EE. The aim of this study is to investigate the non-allergic risk factors for EE. METHODS: This cross-sectional study included subjects who underwent esophagogastroduodenoscopy on a medical health check-up. We compared clinical characteristics between subjects with EE (n = 27) and those without EE (n = 5937). RESULTS: The detection rate of EE was 0.45% (27/5964 persons). Of 27 subjects with EE, 20 subjects were symptomatic and 7 were asymptomatic. On univariate analysis, subjects with EE significantly had higher body mass index (BMI) compared to those without EE; 23.4 (4.4) vs 22.3 (4.5) kg/m2, median (interquartile range), p = 0.005. Endoscopic findings revealed that subjects with EE had significantly higher proportion of hiatal hernia (29.6% vs 14.7%; p = 0.049). Subjects with EE were significantly younger and had higher proportion of bronchial asthma; 45 (11.5) vs 51 (18) years, p = 0.013; 25.9% vs 5.2%, p < 0.001, respectively. Multivariate analysis showed that subjects with EE were positively associated with BMI [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.20; p = 0.010) and hiatal hernia (OR 2.63; 95% CI 1.12-6.18; p = 0.026) compared to those without EE. On trend test, advanced BMI classification had significant trend for increased prevalence of EE (p = 0.002). CONCLUSIONS: Obesity and hiatal hernia may be non-allergic risk factors for EE in Japanese adults.

Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice : ANP for pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice. METHODS: Mice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 µg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-ß (TGF-ß) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor. RESULTS: ANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium-specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-ß stimulation. CONCLUSIONS: ANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.

Identification of a Novel Rhizopus-specific Antigen by Screening with a Signal Sequence Trap and Evaluation as a Possible Diagnostic Marker of Mucormycosis.

Mucormycosis is the second most common mould infection, often indistinguishable from other invasive mould infections such as aspergillosis. Although an appropriate antifungal therapy is effective at an early stage of the infection, there is no reliable diagnostic method for decision making. Thus, it is necessary to develop an efficient method that can detect mucormycosis rapidly and accurately. We searched for secreted or membrane-bound proteins of Rhizopus oryzae, which is the most common pathogen of mucormycosis, using the method of a signal sequence trap by retrovirus-mediated expression (SST-REX). Among the identified proteins, a Rhizopus-specific antigen was selected as a candidate, and efficacy of this specific antigen was evaluated using R. oryzae-infected mice. Of 302 clones obtained from the SST-REX library, a hypothetical protein (23 kDa, named "protein RSA") was selected as a candidate because of its highest prevalence of clones. Protein RSA was detected at significantly higher concentrations in serum and in lung homogenates of the infected mice as compared to those of uninfected mice. Our study indicates that protein RSA may be a promising biomarker of R. oryzae infection. SST-REX may be useful for comprehensive screening of prospective eukaryotic biomarkers of intractable mould infections.

Improved quality of life in asthma patients under long-term therapy: Assessed by AHQ-Japan.

BACKGROUND AND OBJECTIVES: Assessment of the effects of long-term management on patient quality of life (QOL) would be extremely useful for determining asthma treatment strategies. However, no studies have evaluated QOL over an extended period of time. This study evaluated the changes in QOL, drug management and disease severity in the same asthma patients at an interval of approximately 9 years. METHODS: We re-surveyed asthma patients enrolled in a survey conducted in 2004 to evaluate the effects of approximately a decade of treatment on disease severity and QOL assessed by the Japanese Asthma Health Questionnaire (AHQ-JAPAN). RESULTS: A total of 2179 patients were enrolled in the study from 93 centres, and 1332 patients were included in the per-protocol analysis. Usage rates of inhaled corticosteroids (ICS) for treatment of stable asthma were over 90% at both time points. The AHQ-JAPAN total score improved significantly from 22.2±19.7 in 2004 to 19.7±19.9 in 2013 (P<.001). Significant improvements were also observed in 5 of 6 subscales of AHQ-JAPAN, with Social Activity constituting the sole exception. CONCLUSIONS: Asthma severity declined and QOL assessed by AHQ-JAPAN improved, which is considered as a reflection of improved asthma control at least partly attributable to widespread use of anti-inflammatory drugs as represented by ICS. The study also revealed the presence of those with poor QOL, especially in patients with concomitant respiratory diseases, and an increase in severe persistent asthma cases, warranting further long-term efforts at improving QOL. TRIAL REGISTRATION NUMBER: UMIN 000010483.

Down-Regulation of Soluble α-Klotho is Associated with Reduction in Serum Irisin Levels in Chronic Obstructive Pulmonary Disease.

PURPOSE: The klotho gene was originally identified as a putative aging-suppressor gene. Klotho-depleted mice display a shortened life span and exhibit a variety of premature aging-related phenotypes such as pulmonary emphysema and sarcopenia. This study was designed to determine the roles of secreted-type klotho protein on lung and skeletal muscle in chronic obstructive pulmonary disease (COPD). METHODS: Serum α-klotho and irisin levels were assayed in 16 non-smokers, 13 smokers without COPD, and 24 smokers with COPD. Moreover, we examined correlations between soluble α-klotho levels and the results of lung function test, cardiopulmonary exercise test (CPET), and skeletal muscle function in smokers with COPD. RESULTS: Soluble α-klotho levels were significantly lower in smokers with COPD compared to non-smokers and smokers without COPD. In smokers with COPD, those levels did not significantly correlate with any parameters of lung function test. In CPET, peak VO2 significantly correlated with FEV1 (% predicted) (r = 0.76, p = 0.0003) and DLCO (% predicted) (r = 0.62, p = 0.003). In contrast, soluble α-klotho levels did not significantly correlate with peak VO2. Irisin levels were also significantly lower in smokers with COPD. Moreover, there was a significant correlation between soluble α-klotho and serum irisin levels (r = 0.61, p = 0.004). CONCLUSIONS: Our findings could provide a critical first step to understanding the impacts of soluble α-klotho on skeletal muscle in COPD and may lead to the identification of new molecular targets for the treatment of COPD.

Impaired nuclear factor erythroid 2-related factor 2 expression increases apoptosis of airway epithelial cells in patients with chronic obstructive pulmonary disease due to cigarette smoking.

BACKGROUND: Cigarette smoking-induced oxidative stress is known to be a key mechanism in COPD pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor that regulates the antioxidant defense system. The aim of this study was to compare Nrf2 expression in COPD subjects and control subjects, and to determine the role of Nrf2 in protecting against oxidative stress-induced apoptosis. METHODS: We enrolled 8 COPD subjects and 7 control subjects in this study. We performed bronchial brushing by bronchoscopy and obtained bronchial epithelial cells from the airways. Nrf2 expression in bronchial epithelial cells was evaluated by real-time PCR and Western blotting. We examined the effect of 10 or 15 % cigarette smoke extract (CSE) induced A549 cells apoptosis using a time-lapse cell imaging assay with caspase-3/7 activation detecting reagent and performed Terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling assay for confirming A549 cells apoptosis. We also examined the effects of Nrf2 knockdown and, 0.1, 0.5, and 1.0 mM N-acetyl cysteine on CSE-induced apoptosis. Statistical analyses were performed using t-test, paired t-test or an analysis of variance followed by the Tukey-Kramer method. RESULTS: Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects and Nrf2 mRNA were negatively correlated with pack year. Nrf2 protein in COPD subjects was significantly lower than that in control subjects. CSE-induced A549 cells apoptosis was increased in a time-, concentration-dependent manner, and was significantly increased by Nrf2 knockdown. N-acetyl cysteine significantly ameliorated CSE-induced apoptosis. CONCLUSIONS: Nrf2 expression was lower in COPD patients than in control subjects. Nrf2 might have a protective role against apoptosis caused by CSE-induced oxidative stress. These results suggest an involvement of Nrf2 in COPD and administration of antioxidants to patients with COPD might be a basic therapeutic option.

Comparison of the Clinical Courses of Patients with Influenza after Neuraminidase Inhibitors Treatment: A Postcard Survey of the 2013-2014 Influenza Season in Osaka.

Background In Japan, four neuraminidase inhibitors (NAIs) are currently prescribed to patients with influenza A and B. To know the backgrounds and clinical courses of patients with influenza who were treated with NAIs is important in the selection of appropriate medications. Methods We conducted a multicenter observational study in Osaka with postcard questionnaires. Patients who were prescribed NAIs were provided postcard questionnaires containing questions on their backgrounds, body temperatures, and durations of other influenza symptoms. We analyzed the factors that were associated with early fever alleviation using a logistic regression model. Results The postcard response rate was 31% (326 of 1050), and 307 patients were enrolled in this study [150 patients who were under 10 years old (type A, 118; and type B, 32) and 157 patients who were 10 or older (type A, 114; and type B, 43)]. In the patients under 10, the multivariate analysis showed that influenza type (Type B vs Type A; Odds Ratio, 0.13; 95% Confidence Interval: 0.04-0.38) was associated with early fever alleviation. However, NAIs were not related to early fever alleviation. Laninamivir tended to contribute more to early fever alleviation compared to oseltamivir in patients under 10 (Odds Ratio, 2.50;$95% Confidence Interval: 0.90-7.80). Conclusions The types,of prescibed NAIs were not significantly related to early fever alleviation. However, the fever durations of the patients under 10 who were prescribed laninamivir were shorter than those of patients under 10 who were prescribed oseltamivir or zanamivir.

Molecular Epidemiological Study on Passive Smoking and Estrogen Receptor Expression in Never-smokers with Non-small Cell Lung Cancer.

Background: Although sex hormones are thought to play an important role in the carcinogenesis of non-small cell lung cancer (NSCLC) in never-smokers, the causative mechanism remains unknown. Passive smoking (PS) is common among East Asian women and has been suggested to be a potential cause of the disease. Methods: We systematically evaluated the expression of estrogen receptor (ER), the prevalence of PS, and genetic mutations using tumor samples from a prospectively registered cohort of never-smokers with lung cancer. The study enrolled 92 never-smokers with NSCLC. Expression of ERa, ERP, and progesterone receptor (PR) was examined via immunohistochemical staining (IHC). Detailed PS information was obtained through a standardized questionnaire. The cumulative dose of PS (CPS) was evaluated as a sum of the number of exposure years at home and/or in the work place. Results: Nuclear expression of ERa, ERP, and PR was detected in 0, 14, and 3 cases, respectively. ERP was more frequently overexpressed in earlier stage cancer (p=0.043). Ninety patients (97.9%) had a PS history, and the median CPS was 47.5 years (range, 0-103 years). There was no significant correlation between the amount of PS -and ERP expression (p=0.101). Twelve patients (85.7%) had Epidermal growth factor receptor ,EGFR) mutations in 14 .tumors expressing ERP, and a trend towards an association between ERP expression and EGFR mutations (p =0.067) was -observed. Conclusions: Nuclear expression of ERP was more frequently observed in early stage NSCLC in never-smokers.

Up-regulation of the MicroRNA miR-30c Induced by High Mobility Group Box 1 in A549 Cells Used as an Alveolar Epithelial Model.

Background: MicroRNAs (miRNAs) have been reported to be involved in multiple diseases, including chronic obstructive pulmonary disease (COPD), a progressive disease in which alveolar apoptosis may play a role. We hypothesized that miRNAs are associated with the response to injury. induced by high mobility group box 1 (HMGB1), a cytokine crucial for the development of COPD, and studied the potential link between HMGB1 and miRNAs. Materials and Methods: A549 cells were stimulated with recombinant HMGB1. RNA and protein were extracted and culture supernatants were collected. Molecules downstream of HMGB1 signaling were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Expression levels of miRNA were analyzed by quantitative RT-PCR. Cellular injury was evaluated by western blotting of relevant proteins. Apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL). Results: HMGB1 treatment of A549 cells resulted in the up-regulation of tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 mRNAs and over expression of matrix metalloprotease (MMP)-7 protein in the supernatant. The miRNA miR-30c was also up-regulated in response to HMGB1 treatment. Cellular injury and apoptosis were observed following HMGB1 treatment, as demonstrated by the oyerexpression of cyclin A2 (CCNA2) and phosphatase and tensin homolog (PTEN) proteins and-b'y decreased levels of pro-caspase-7 protein. The TUNEL assay showed that A549 cells with HMGB1 stimulation underwent apoptosis. Conclusions: Up-regulation of miR-30c and apoptosis of A549 cells were observed following HMGB1 stimulation. Our model demonstrates the potential for utilization of HMGB1 and miR-30c in further studies of alveolar apoptosis in COPD.

Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD. METHODS: We measured the serum irisin level in 72 COPD patients and 27 control subjects, and investigated its correlation to pulmonary function parameters, exercise capacity and physical activity level. In addition, we analysed the effects of acute and chronic exercise on serum irisin level. RESULTS: Fat-free mass index was not significantly different between the two study groups. However, lower serum irisin level was observed in COPD patients than in the control subjects (COPD patients: median (interquartile range) 31.6 (22.7-40.4) ng/mL; control subjects: 50.7 (39.3-65.8) ng/mL; P < 0.001). The serum irisin level did not significantly correlate with any pulmonary function parameters and 6-min walk distance. However, serum irisin level was associated with the physical activity level in all subjects. In COPD patients, acute exercise did not affect serum irisin level, but an 8-week exercise training was linked to the significant increase in its level. CONCLUSIONS: Circulating irisin could be used to evaluate physical activity in COPD patients and increased after an 8-week exercise training. Serum irisin level may prove to be a valuable biomarker in clinical follow up of COPD.

Effect of Intratracheal Administration of Adipose-derived Stromal Cells on Bleomycin-induced Lung Injury in a Rat Model.

BACKGROUND: Mesenchymal stromal cells (MSCs) have been intensively investigated in regenerative medicine. Among the different types of MSCs, adipose tissue-derived stromal cells (ASCs) can be obtained with relatively less invasive techniques. Since ASC administration is a candidate strategy for the treatment of refractory diseases including pulmonary fibrosis, we investigated whether intratracheal injection of ASCs had therapeutic potential against bleomycin (BLM)-induced lung injury in rats. METHODS: BLM was intratracheally administered to rats, and 1 week later ASCs were harvested. Two weeks after BLM treatment, ASCs or phosphate-buffered saline (PBS) were injected autologously into the rats via the trachea A semi-quantitative histological evaluation was conducted to assess the injured lungs, followed by cell tracing at 3 or 6 weeks after BLM instillation. RESULTS: ASC administration did not affect the severity of lung damage on the third week after BLM exposure, but prevented further aggravation of the lung injury, as apparent on the sixth week. A fluorescent cell tracer revealed that the majority of ASCs did not appear to have penetrated inside the lung region injured by BLM on the third week after BLM instillation, but some of these cells sprouted deep into the thick distorted architecture of the injured lung on the sixth week after the BLM instillation. CONCLUSIONS: The results of the present study suggest that ASCs may play a role in the prevention of ongoing aggravation of lung injury in the long term.

Pentraxin-3 as a Biomarker for Febrile Neutropenia in Patients with Lung Cancer.

BACKGROUND: Pentraxin-3 (PTX3) is a newly discovered biomarker for various inflammatory conditions. We measured plasma PTX3 levels in patients with febrile neutropenic lung cancer and examined the utility of PTX3 levels as a biomarker for febrile neutropenia. METHODS: Fourteen patients with febrile neutropenic lung cancer were enrolled in the study. In addition, 10 untreated lung cancer patients and 12 healthy adults were enrolled as a disease control group and a healthy control group, respectively. On the day of onset of febrile neutropenia (day 1) and days 3 and 7, PTX3 and C-reactive protein (CRP) levels were measured. In the control groups, PTX3 and CRP levels were measured once. RESULTS: On day 1, plasma CRP levels in febrile neutropenia during chemotherapy or chemoradiotherapy for lung cancer (FN/LC) patients (8.11 ± 6.42 mg/dL) were significantly higher than those in healthy controls (HC) and chemotherapy/chemoradiotherapy-naïve lung cancer (CN/LC) patients (p < 0.05). However, CRP levels of the CN/LC group (0.33 ± 0.02 mg/dL) were also significantly higher than those of the HC group (0.07 ± 0.09 mg/dL) (p < 0.05). In contrast, plasma PTX3 levels of the FN/LC group (6.14 ± 5.28 ng/mL) were significantly higher than those of the HC and CN/LC groups on day 1 (p < 0.05), but PTX3 levels of the CN/LC group (1.60 ± 0.64 ng/mL) were not significantly higher than those of the HC group (1.05 ± 0.25 ng/mL). In the FN/LC group, PTX3 levels peaked immediately on day 1. CONCLUSIONS: PTX3 may be a useful biomarker for diagnosis of FN in patients with LC.

The Macroscopic Appearance of Computed Tomography-guided Needle Biopsy Specimens Correlates with Tumor Metastasis in Non-small Cell Lung Cancer.

BACKGROUND: Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC). METHODS: A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis. RESULTS: In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026). CONCLUSIONS: These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.

Epistatic effects of multiple receptor genes on pathophysiology of asthma - its limits and potential for clinical application.

To date, genome-wide association studies (GWAS) permit a comprehensive scan of the genome in an unbiased manner, with high sensitivity, and thereby have the potential to identify candidate genes for the prevalence or development of multifactorial diseases such as bronchial asthma. However, most studies have only managed to explain a small additional percentage of hereditability estimates, and often fail to show consistent results among studies despite large sample sizes. Epistasis is defined as the interaction between multiple different genes affecting phenotypes. By applying epistatic analysis to clinical genetic research, we can analyze interactions among more than 2 molecules (genes) considering the whole system of the human body, illuminating dynamic molecular mechanisms. An increasing number of genetic studies have investigated epistatic effects on the risk for development of asthma. The present review highlights a concept of epistasis to overcome traditional genetic studies in humans and provides an update of evidence on epistatic effects on asthma. Furthermore, we review concerns regarding recent trends in epistatic analyses from the perspective of clinical physicians. These concerns include biological plausibility of genes identified by computational statistics, and definition of the diagnostic label of 'physician-diagnosed asthma'. In terms of these issues, further application of epistatic analysis will prompt identification of susceptibility of diseases and lead to the development of a new generation of pharmacological strategies to treat asthma.

Analysis of the contributing factors to airway hyperresponsiveness by a forced oscillation technique in patients with asthma.

BACKGROUND: Forced oscillation technique (FOT) is increasingly used to obtain much information on the state of the respiratory system. However, there are little data about FOT parameters on methacholine provocation test in adult asthma. This study was designed to determine the physiological implications of FOT parameters during methacholine provocation and analyze the major contributing factors to airway hyperresponsiveness (AHR) in asthma. METHODS: Spirometry and FOT were performed in 22 asthmatic patients and 21 normal control subjects before and after provocation with a maximal dose of methacholine. RESULTS: In asthmatic patients, the percent increase in resistance at 5 Hz (R5) and resistance at 20 Hz (R20) after the methacholine provocation was 70 [45-93] % and 16 [5-23] %. The percent change in R20 was not significantly correlated with the percent change in FVC or FEV1. Similarly, the percent change in R5 was not significantly correlated with the percent change in FEV1, but was significantly correlated with the percent change in FVC. Moreover, the percent change in R5 was significantly correlated with the closing index (r = 0.55, p = 0.01). In addition, AHR to methacholine was closely correlated with the percent change in R5 (r = -0.71, p = 0.001). CONCLUSIONS: Simultaneous measurement of FOT and bronchial challenge test provide meaningful information, and greater change in R5 may represent exaggerated response of small airways in asthmatic patients. This study will provide new insights into the physiological implications of each FOT parameter in asthmatic patients.

[Cognitive function in patients with chronic obstructive pulmonary disease].

It is increasingly recognized that COPD is a multi-component disease, but little attention has been paid to its effects on cognition. Cognitive dysfunction is associated with increased disability of daily living and mortality. However, it remains to be elucidated in COPD. Our main findings are: 1) cognitive dysfunction in patients with COPD is related to the grade of activity of daily livings and hypoxemia, especially in exercise-induced hypoxemia; 2) cognitive impairment such as perception, attention and short memory are impaired; 3) attention function determined by Trail Making Test is improved by O2 inhalation with the increase in the prefrontal cortex oxygenation; 4) by 8 week exercise training, cognitive function in COPD is improved with the increase in the prefrontal circulation.

Reaction of plasma adiponectin level in non-small cell lung cancer patients treated with EGFR-TKIs.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used to treat advanced non-small cell lung cancer (NSCLC) patients with activated EGFR mutations, and are associated with excellent response and improvement of performance status. Adipose tissue produces and releases substances called adipokines, which include adiponectin, leptin, resistin, and hepatocyte growth factor (HGF), etc. Previously, we reported that high levels of plasma HGF at diagnosis indicated intrinsic resistance to EGFR-TKIs. EGFR-TKIs have been hypothesized to affect these adipokines. METHODS: This prospective study, to evaluate the correlation between plasma adiponectin and insulin levels and non-hematological adverse effects in advanced NSCLC following EGFR-TKIs administration, was conducted at the Osaka City University Hospital. Plasma adiponectin and insulin levels were determined at diagnosis and on treatment day 30. RESULTS: Overall 33 patients were enrolled. We obtained plasma samples for analyses from all patients at diagnosis and from 26 patients on day 30. Increased adiponectin (13.69 to 14.42 microg/mL, p = 0.0092), and decreased insulin (404.0 to 351.2 pg/mL, p = 0.022) were observed after EGFR-TKI treatments. High levels of adiponectin at diagnosis were associated with severities of skin rash (p = 0.035). CONCLUSIONS: The adiponectin was affected by EGFR-TKI treatments for NSCLC. Besides, the adverse events by EGFR-TKIs were influenced by the plasma adipokines at diagnosis. Our study may provide useful information regarding patient outcomes to EGFR-TKI treatments. A prospective large clinical trial is warranted to clarify these results.