Tsuneyuki Takahashi

Protection against bradykinin-induced bronchoconstriction in asthmatic patients by neurokinin receptor antagonist

Axon reflex mechanisms may be involved in the pathogenesis of asthma, but there has been no direct evidence that endogenous tachykinins cause bronchoconstriction in asthmatic subjects. We have studied the effect of a tachykinin receptor antagonist (FK-224) on bronchoconstriction induced by inhalation of bradykinin in asthmatic patients. In a double-blind, placebo-controlled, crossover trial, ten subjects with stable asthma were given FK-224 (4 mg) or placebo by inhalation 20 min before challenge with bradykinin (0-1250 micrograms/ml, five breaths of each concentration) given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK-224 significantly opposed the bronchoconstrictor effect; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5.3 micrograms/ml after placebo and 40 micrograms/ml after FK-224 (p < 0.001). Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK-224 in all three. Antagonism of the tachykinin receptor by FK-224 greatly inhibited both bronchoconstriction and coughing induced by bradykinin in asthmatic patients, suggesting that tachykinin release from the airway sensory nerves is involved in responses to bradykinin. Tachykinin receptor antagonists may be useful in the treatment of asthma.

Underdiagnosis and undertreatment of COPD in primary care settings

Objective:  The aim of this study was to improve the detection of COPD in a primary care setting and to evaluate the subsequent management of these patients by general practitioners.

Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways

To examine the role of endogenous nitric oxide in allergic airway inflammation, we investigated the effect of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (l-NAME), on antigen-induced airway microvascular leakage in actively sensitized guinea pigs by using Evans blue dye. Three weeks after sensitization with ovalbumin (10 micrograms), the tracheas were cannulated, and lungs were artificially ventilated. Animals were pretreated with atropine and propranolol (both 1 mg/kg, intravenously) to avoid neural modification. Ovalbumin inhalation (3 mg/ml, 1 minute) challenge caused significant microvascular leakage in all airways portions, which was significantly suppressed in a dose-dependent manner by pretreatment with intravenous injection of L-NAME (1 and 10 mg/kg) but not with the inactive enantiomer D-NAME (10 mg/kg). This inhibition by L-NAME was significantly reversed by co-administration of L-arginine (100 mg/kg, intravenously). Pretreatment with a vasoconstrictor, phenylephrine (20 micrograms/kg, intravenously), had no inhibitory effects on antigen-induced airway microvascular leakage despite increasing systemic blood pressure. Inhalation of representative mast cell-derived mediators, histamine (2 mg/ml, 1 minute) or leukotriene D4 (5 micrograms/ml, 1 minute), produced significant microvascular leakage in all airways. L-NAME (10 mg/kg, intravenously) partially but significantly inhibited leukotriene D4-induced leakage, whereas histamine-induced leakage was not affected. These results suggest that endogenous nitric oxide acts to increase airway microvascular leakage after airway allergic reaction.

Biomarker-based detection of asthma–COPD overlap syndrome in COPD populations

Asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) was proposed by the science committees of both Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD). However, the definition of ACOS has remained unclear all over the world, and the prevalence rate of ACOS is basically dependent on the patient’s symptoms or the physician’s opinion, based on questionnaire testing. In the current case report, we investigated the prevalence rate of COPD patients with high levels of fractional exhaled nitric oxide (FENO) or immunoglobulin E (IgE) as candidate markers of ACOS in COPD, as a multicenter, cross-sectional study. Outpatients with COPD were enrolled from Tohoku University Hospital, Sendai, Japan, and five hospitals (Tohoku University Hospital, Sendai, Japan; NTT East Tohoku Hospital, Sendai, Japan; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to February 28, 2014. When they were estimated using 35 ppb as the cutoff value of FENO, the prevalence rate of ACOS was 16.3% in COPD. When estimated by both FENO and IgE, the high-FENO/high-IgE group was 7.8% in COPD. To the best of our knowledge, this study is the first to detect the prevalence rate of ACOS in COPD populations by using objective biomarkers. The results from the current study should be useful to identify the subgroup requiring early intervention by inhaled corticosteroids/long-acting beta agonist combination in COPD in order to improve the long-term management for ACOS.

Relationship between cholinergic airway tone and serum immunoglobulin E in human subjects

It has recently been shown that immunoglobulin (Ig)E facilitates the cholinergic bronchoconstrictor pathway in human tissue in vitro. However, whether this occurs in humans in vivo has not been clarified. In this study, the bronchodilator responses were examined to inhalation of a submaximal dose of the anticholinergic agent oxitropium bromide (600 microg) in normal and allergic subjects with various levels of total serum IgE. Values of the forced expiratory volume in one second (FEV1) for all subjects were greater than 80% of predicted, but were negatively correlated with serum IgE levels (p<0.01). Oxitropium bromide inhalation induced an increase in FEV1 that was significantly greater in allergic rhinitis patients with high serum IgE (155+/-20 mL (mean+/-SEM), p<0.05) than in healthy subjects (64+/-21 mL) or those with allergic rhinitis but low serum IgE (82+/-21 mL, p<0.05). In contrast, the effects of the inhaled beta2-adrenergic agent orciprenaline sulphate (2.25 mg) were not significantly different among the three groups. In conclusion, higher serum immunoglobulin E levels were correlated with lower values of the forced expiratory volume in one second, and anticholinergic agents, but not beta2-adrenergic agents, caused more pronounced bronchodilation in subjects with high than in those with low immunoglobulin E levels. These data suggest that serum immunoglobulin E may be one of the factors that determine the airway tone, possibly via cholinergic mechanisms.

Coexisting COPD in elderly asthma with fixed airflow limitation: assessment by DLco %predicted and HRCT

ABSTRACT Background: Asthma patients with fixed airflow limitation (FL) are theoretically classified into two phenotypes, that is, coexisting chronic obstructive pulmonary disease (COPD) and asthmatic airway remodeling. However, the precise percentages of such patients are not known. Objective: To assess the prevalence of patients with both FL and COPD components in elderly asthma. Methods: We evaluated patients by lung diffusion impairment and emphysematous findings in high-resolution computed tomography (HRCT) as candidates for COPD components, as a multicenter, cross-sectional survey. Asthma outpatients ≥ 50 years of age were enrolled from Tohoku University Hospital, Sendai, Japan, and four hospitals (Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai, JAPAN; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to November 30, 2014. Results: The prevalence of patients with FEV1/FVC <70% was 31.0% of those in their 50s, 40.2% of those in their 60s and 61.9% of those in their 70s or older. The prevalence of those patients with lung diffusion impairment (i.e. the percent predicted values of diffusing capacity of the lung for carbon monoxide (DLco %predicted) <80%) or emphysematous findings in HRCT (i.e. the appearance of low attenuation area (LAA)) was 18.3% of those in their 50s, 13.8% of those in their 60s and 35.7% of those in their 70s or older. Conclusions: Nearly half of the patients with FL in elderly asthma show coexisting COPD components when assessed by DLco %predicted and LAA in HRCT.

Stratifying the risk of COPD exacerbation using the modified Medical Research Council scale: A multicenter cross-sectional CAP study

1016/j.resinv.2014.10.006 he Japanese Respiratory Society. Published by Else of Internal Medicine, Wakayama Medical Universit n; c National Hospital Organization Wakayama Hos raduate School of Medicine, Japan; f Kamei Respirator al, Japan; i NTT East Tohoku Hospital, Japan; j Hirosh spital, Japan; l Minami Tokushima Clinic, Japan; m Hir n; o Tohoku Rosai Hospital, Japan. uthor. Tel.: þ81 73 441 0619; fax: þ81 73 447 2201. kazmatsu@wakayama-med.ac.jp (K. Matsunaga) a-med.ac.jp (K. Akamatsu), tsuna@wakayama-m .pikara.ne.jp (T. Kamei), tsudat@k-you.or.jp (T. Ts i@east.ntt.co.jp (T. Takahashi), hozawa@vesta.ocn ikara.ne.jp (Y. Sakamoto), hrkjmsom@air.ocn.ne.j izusawa.iwate.jp (U. Katsumata), mmiura@tohok hoku.ac.jp (M. Ichinose). by physicians is limited [3], and there is a need for a simple assessment tool that can be used in everyday practice [4]. The modified Medical Research Council (mMRC) scale is a wellvalidated questionnaire that uses a simple grading system to quantify disability associated with breathlessness [5], and current guidelines advocate the use of this scale to assess

Physical inactivity is associated with decreased growth differentiation factor 11 in chronic obstructive pulmonary disease

Background Growth differentiation factor 11 (GDF11) is reported to possess anti-aging and rejuvenating effects, including muscle regeneration and to be highly expressed in skeletal muscle. Recently, we demonstrated that the levels of plasma GDF11 were decreased in COPD. However, the effect of decreased circulating GDF11 in the pathophysiology of COPD remains unknown. The aim of this study is to investigate the association between the plasma GDF11 levels and various clinical parameters in patients with COPD. Patients and methods Eighteen ex-smokers as control subjects and 70 COPD patients participated in the current study. We measured the levels of plasma GDF11 using immunoblotting, lung function, physical activity using a triaxial accelerometer, quadriceps strength, exercise capacity, and systemic inflammatory markers. We investigated the association between the levels of plasma GDF11 and these clinical parameters. Results The levels of plasma GDF11 in the COPD patients had significant positive correlations with the data of lung function. Furthermore, the levels of plasma GDF11 were significantly correlated with the physical activity, quadriceps strength, and exercise capacity. Moreover, the levels of plasma GDF11 were significantly correlated with the data of inflammatory markers. Although various factors were related to GDF11, the multiple regression analysis showed that physical activity was significantly associated with the levels of plasma GDF11. Conclusion Physical inactivity was significantly related to the decreased GDF11 levels in COPD, which might be useful for understanding the pathogenesis of COPD. Clarifying the relationships between the physical inactivity and GDF11 may reveal a potentially attractive therapeutic approach in COPD via increasing the plasma levels of GDF11.