Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases.

Extracellular lysophospholipids (lysophosphatidic acid, lysophosphatidylcholine, sphingosine 1-phosphate, etc.), which are synthesized from phospholipids in the cell membrane, act as lipid mediators, and mediate various cellular responses in constituent cells in the respiratory system, such as contraction, proliferation, migration, and cytoskeletal organization. In addition to these effects, the expression of the adhesion molecules is enhanced by these extracellular lysophospholipids in pulmonary endothelial cells. These effects are exerted via specific G protein-coupled receptors. Rho, Ras, and phospholipase C (PLC) have been proven to be their signaling pathways, related to Ca2+ signaling due to Ca2+ dynamics and Ca2+ sensitization. Therefore, lysophospholipids probably induce pulmonary vascular remodeling through phenotype changes in smooth muscle cells, endothelial cells, and fibroblasts, likely resulting in acute respiratory distress syndrome due to vascular leak, pulmonary hypertension, and pulmonary fibrosis. Moreover, lysophospholipids induce the recruitment of inflammatory cells to the lungs via the enhancement of adhesion molecules in endothelial cells, potentially leading to the development of asthma. These results demonstrate that lysophospholipids may be novel therapeutic targets not only for injury, fibrosis, and hypertension in the lung, but also for asthma. In this review, we discuss the mechanisms of the effects of lysophospholipids on the respiratory system, and the possibility of precision medicine targeting lysophospholipids as treatable traits of these diseases.

Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.

Airway Smooth Muscle Regulated by Oxidative Stress in COPD.

Since COPD is a heterogeneous disease, a specific anti-inflammatory therapy for this disease has not been established yet. Oxidative stress is recognized as a major predisposing factor to COPD related inflammatory responses, resulting in pathological features of small airway fibrosis and emphysema. However, little is known about effects of oxidative stress on airway smooth muscle. Cigarette smoke increases intracellular Ca2+ concentration and enhances response to muscarinic agonists in human airway smooth muscle. Cigarette smoke also enhances proliferation of these cells with altered mitochondrial protein. Hydrogen peroxide and 8-isoprostans are increased in the exhaled breath condensate in COPD. These endogenous oxidants cause contraction of tracheal smooth muscle with Ca2+ dynamics through Ca2+ channels and with Ca2+ sensitization through Rho-kinase. TNF-α and growth factors potentiate proliferation of these cells by synthesis of ROS. Oxidative stress can alter the function of airway smooth muscle through Ca2+ signaling. These phenotype changes are associated with manifestations (dyspnea, wheezing) and pathophysiology (airflow limitation, airway remodeling, airway hyperresponsiveness). Therefore, airway smooth muscle is a therapeutic target against COPD; oxidative stress should be included in treatable traits for COPD to advance precision medicine. Research into Ca2+ signaling related to ROS may contribute to the development of a novel agent for COPD.

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic.

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

[A CASE OF BRONCHIAL ASTHMA CAUSED BY EXPOSURE TO ASPERGILLUS ORYZAE IN A JAPANESE RICE WINE BREWERY WORKER].

A-55-year-old man who have been working in a Sake (Japanese rice wine) brewer for 27 years, came to the outpatient clinic because cough, dyspnea, and wheeze gradually worsen. These symptoms occurred immediately after exposure to Aspergillus oryzae in the brewing process since age 43. A dust mask was required to reduce these symptoms, but that work was interrupted by exacerbation of these symptoms. These symptoms disappeared when he was away from the on-site work. The SMART therapy using combined inhaler of budesonide (ICS) with formoterol (LABA) was effective to reduce these symptoms. In serological test total IgE antibody and Aspergillus specific IgE antibodies increased, whereas Aspergillus precipitating antibody and Asp f 1 (a major allergen of Aspergillus fumigatus) specific IgE antibody were negative. Eosinophilia in peripheral blood was not observed, and FeNO was not increased. Values of peak expiratory flow was reduced by 20.8% after exposure to Aspergillus oryzae in that work. Lung function test including reversibility test was intact, but FEV1 was fluctuated up to 400mL (15.9%) in the clinical course. Based on these variable clinical manifestations, laboratory data, and lung function test findings, this case was diagnosed as adult-onset atopic (Aspergillus-sensitized) bronchial asthma without allergic bronchopulmonary aspergillosis. Involvement of eosinophilic inflammation is unknown. Allergen may be considered to be Aspergillus oryzae, because these symptoms do not occur in any environment without exposure to Aspergillus oryzae. This patient is the first case of occupational asthma related to Aspergillus oryzae in a Japanese rise wine brewer.

[A CASE OF ALLERGIC RHINITIS WHO HAS DEVELOPED EOSINOPHILIC PNEUMONIA, FOLLOWED BY EOSINOPHILIC CELLULITIS].

A-68-year-old man, who has allergic rhinitis with peripheral blood eosinophilia, hospitalized because of fever of unknown origin in May 2020. Five days after antibiotics were given, itchy exanthema occurred, followed by gland glass opacity on both lungs with bilateral pleural effusions. Since acute respiratory failure developed, bronchoscopy was hard to carry out. However, this case was considered acute eosinophilic pneumonia induced by antibiotics, based on radiological findings and laboratory data. Therefore, steroid pulse therapy using intravenous administration of methylprednisolone started, and this therapy was effective. Since these chest shadows and hypoxia were disappeared in two weeks, the amount of steroid was gradually reduced, however, eosinophilic pneumonia recurred once during this course. After discharge in June 2020, this patient came to the outpatient department. When oral administration of prednisolone was decreased less than 2.5mg/day, redness and swelling with slight itch were appeared in the left forearm in September 2020. Histological findings from shin biopsy showed that eosinophils excessively invade to the dermis without angiitis. Although flame figure was not observed in the specimen, we considered that this case has developed eosinophilic cellulitis, based on the clinical manifestation and pathological findings. When prednisolone was increased to 30mg/day, these symptoms were improved, and then prednisolone was gradually reduced. After that, recurrences of these diseases did not occur during the observation period. This case may be diagnosed as hypereosinophilic syndrome since eosinophilic pneumonia and eosinophilic cellulitis caused continuously by recruitment of eosinophils to lung and skin.

Role of Airway Smooth Muscle in Inflammation Related to Asthma and COPD.

Airway smooth muscle contributes to both contractility and inflammation in the pathophysiology of asthma and COPD. Airway smooth muscle cells can change the degree of a variety of functions, including contraction, proliferation, migration, and the secretion of inflammatory mediators (phenotype plasticity). Airflow limitation, airway hyperresponsiveness, ß2-adrenergic desensitization, and airway remodeling, which are fundamental characteristic features of these diseases, are caused by phenotype changes in airway smooth muscle cells. Alterations between contractile and hyper-contractile, synthetic/proliferative phenotypes result from Ca2+ dynamics and Ca2+ sensitization. Modulation of Ca2+ dynamics through the large-conductance Ca2+-activated K+ channel/L-type voltage-dependent Ca2+ channel linkage and of Ca2+ sensitization through the RhoA/Rho-kinase pathway contributes not only to alterations in the contractile phenotype involved in airflow limitation, airway hyperresponsiveness, and ß2-adrenergic desensitization but also to alteration of the synthetic/proliferative phenotype involved in airway remodeling. These Ca2+ signal pathways are also associated with synergistic effects due to allosteric modulation between ß2-adrenergic agonists and muscarinic antagonists. Therefore, airway smooth muscle may be a target tissue in the therapy for these diseases. Moreover, the phenotype changing in airway smooth muscle cells with focuses on Ca2+ signaling may provide novel strategies for research and development of effective remedies against both bronchoconstriction and inflammation.

Eosinophil Inflammation and Hyperresponsiveness in the Airways as Phenotypes of COPD, and Usefulness of Inhaled Glucocorticosteroids.

Background: The differential diagnosis in persistent airway limitation is sometimes not so clear in older adults. Airway eosinophilia and airway hyperresponsiveness may develop in some cases with chronic obstructive lung disease (COPD), independent of asthma. However, little is known about clinical significance of these phenotypes of COPD in detail. Aims and objectives: This clinical study was designed to examine prevalence of airway eosinophilia and airway hyperresponsiveness in COPD who have no symptom and no past history of asthma, and to examine involvement of these pathophysiological features of asthma in the management and therapy for COPD. Methods: Sputum examination via qualitative and quantitative procedures was performed in stable COPD (GOLD 1-3). When sputum eosinophils were qualitatively (≥+) or quantitatively assessed (≥3%), ciclesonide (inhaled glucocorticosteroids) was added on bronchodilators. In cases with FEV1 ≥ 70% of predicted values, acetylcholine provocation test was examined for assessment of airway hyperresponsiveness. Therapeutic effect was evaluated using spirometry and COPD assessment test (CAT). Results: Sputum eosinophils were observed in 65 (50.4%) of 129 subjects using qualitative analysis; in contrast, lower grade (>0%) and higher grade (≥3%) were observed in 15 (20.3%) and 25 (33.8%) of 74 subjects using quantitative analysis. Airway hyperresponsiveness developed in 46.9% of these subjects with sputum eosinophils. Exacerbations occurred much more frequently in lower-grade airway eosinophilia without ciclesonide than in higher-grade airway eosinophilia with ciclesonide. Airway hyperresponsiveness significantly increased frequency of exacerbations in COPD with both lower and higher grade in airway eosinophilia. Addition of ciclesonide to indacaterol markedly improved lung function (FEV1, IC), CAT score, and reliever use in these subjects with airway eosinophilia determined by qualitative analysis. However, ciclesonide was less effective in improving these values in subjects with airway hyperresponsiveness than in those without airway hyperresponsiveness. Conclusions: Airway eosinophilia and airway hyperresponsiveness are complicated with 25-50% of COPD that have no symptom and history for asthma. These phenotypes of COPD are closely related to symptom stability and reactivity to glucocorticosteroids. These phenotypes may play key roles for advancement of the management and therapy of this disease.

Characteristics and association with survival of respiratory-related hospitalization in Japanese idiopathic pulmonary fibrosis patients.

BACKGROUND: The characteristics and significance of respiratory-related hospitalization in patients with idiopathic pulmonary fibrosis (IPF) in Asian countries remain unknown. The purpose of this study was to define the characteristics of respiratory-related hospitalization and to inspect the relationship between respiratory-related hospitalization and subsequent survival in patients with IPF in Japanese general practice. METHODS: Patients with IPF who underwent clinical evaluation between February 2008 and August 2017 were screened. Only those who had undergone evaluation within 1 year after the diagnosis of IPF were included in the study. The post-diagnosis pulmonary function tests were considered the registration point. We then performed a 6-month landmark analysis including only patients who were alive 6 months after the registration. The characteristics of respiratory-related hospitalizations during the 6 months after registration and the association between respiratory-related hospitalization and survival were investigated. RESULTS: A total of 106 patients with IPF were included in the study. The mean forced vital capacity (FVC) at registration was 80.2 ± 25.1% predicted. Seventeen patients (16.0%) had respiratory-related hospitalization during the 6 months after registration. Pneumonia was the most frequent reason for hospitalization (47.0%), followed by acute exacerbation of IPF (29.4%). In multivariate analysis, % predicted FVC (hazard ratio: 0.98, 95% confidence interval: 0.96-0.99, p = 0.004), 6-month decrease in % predicted FVC (1.05, 1.02-1.08, 0.005), and respiratory-related hospitalization (2.45, 1.24-4.85, 0.009) were significantly associated with survival. CONCLUSIONS: Pneumonia is the most frequent cause of respiratory-related hospitalization in Japanese IPF patients. Furthermore, respiratory-related hospitalization is significantly associated with subsequent poor survival.

Involvement of Allosteric Effect and KCa Channels in Crosstalk between ß2-Adrenergic and Muscarinic M2 Receptors in Airway Smooth Muscle.

To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between ß2-adrenergic and muscarinic M2 receptors, focusing on allosteric effects and G proteins/ion channels coupling. Muscarinic receptor antagonists (tiotropium, glycopyrronium, atropine) synergistically enhanced the relaxant effects of ß2-adrenergic receptor agonists (procaterol, salbutamol, formoterol) in guinea pig trachealis. This crosstalk was inhibited by iberitoxin, a large-conductance Ca2+-activated K⁺ (KCa) channel inhibitor, whereas it was increased by verapamil, a L-type voltage-dependent Ca2+ (VDC) channel inhibitor; additionally, it was enhanced after tissues were incubated with pertussis or cholera toxin. This synergism converges in the G proteins (Gi, Gs)/KCa channel/VDC channel linkages. Muscarinic receptor antagonists competitively suppressed, whereas, β2-adrenergic receptor agonists noncompetitively suppressed muscarinic contraction. In concentration-inhibition curves for β2-adrenergic receptor agonists with muscarinic receptor antagonists, EC50 was markedly decreased, and maximal inhibition was markedly increased. Hence, muscarinic receptor antagonists do not bind to allosteric sites on muscarinic receptors. ß2-Adrenergic receptor agonists bind to allosteric sites on these receptors; their intrinsic efficacy is attenuated by allosteric modulation (partial agonism). Muscarinic receptor antagonists enhance affinity and efficacy of ß2-adrenergic action via allosteric sites in ß2-adrenergic receptors (synergism). In conclusion, KCa channels and allosterism may be novel targets of bronchodilator therapy for diseases such as asthma and COPD.

Physical activity in daily life in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive impairment of lung function and degradation of daily activity; however, this degradation has not been adequately elucidated. The objective of this study was to measure the physical activity of patients with IPF to determine its relationships with physiological parameters and survival rate. METHODS: In total, 31 patients with IPF and 20 age-matched healthy participants were enrolled in this study. Physical activity was assessed using a physical activity monitor. The relationships among physical activity, physiological data, questionnaire-based patient-centered data, and survival were examined. RESULTS: Physical activity, expressed as daily activity energy expenditure (AEE), was significantly lower, and the percentage of sedentary time was significantly longer in patients with IPF than in healthy participants. Moreover, AEE was moderately correlated with body-mass index, forced vital capacity, diffusing capacity of carbon monoxide, and partial arterial pressure of oxygen. Relatively strong correlation was also observed between AEE and the 6-min walk distance, but not with daily dyspnea, depression, and health-related quality of life scores. Prognostic analysis indicated that daily AEE was a significant predictor of survival. CONCLUSIONS: Patients with IPF were significantly inactive compared with age-matched healthy participants. In patients with more impaired physiological functions, the lower the physical activity was, the more was the sedentary time increased. Furthermore, lower daily physical activity resulted in significantly worse survival.

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.

Fat-free mass index predicts survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Detailed body composition, such as fat-free mass, has not been examined in idiopathic pulmonary fibrosis (IPF). We investigated whether the fat-free mass index (FFMI), an index of lean body mass, predicted survival. METHODS: Forty-four patients with IPF were enrolled in the study. Their body composition was assessed using direct segmental multi-frequency bioelectrical impedance analysis. The degree of correlation between variables of body composition and other variables such as forced vital capacity (FVC) and survival was examined. RESULTS: There was a significant positive correlation between FFMI and FVC, diffusion capacity of the lung for carbon monoxide (DLCO ) and 6-min walk distance, and a significant negative correlation with age. However, there was no significant correlation between FFMI and percentage predicted FVC or DLCO , with the degree of correlation being similar to that observed for BMI. The mean observation period in the survival analysis was 837.5 ± 407.5 days. A univariate Cox proportional hazard model showed that several variables, but not BMI, were associated significantly with survival. FFMI (hazard ratio (HR): 0.64, 95% CI: 0.43-0.94, P = 0.02) and percentage predicted FVC (HR: 0.96, 95% CI: 0.93-0.99, P=0.008) were significant factors in a multivariate model. CONCLUSION: We conclude that FFMI is a significant independent predictor of survival in patients with IPF.

Clinical Features and Outcomes of IPF Patients Hospitalized for Pulmonary Infection: A Japanese Cohort Study.

Many patients with idiopathic pulmonary fibrosis (IPF) undergo hospitalizations due to pulmonary infections. We retrospectively investigated the characteristics of hospitalizations due to pulmonary infection in patients with IPF to elucidate causative pathogens and mortality. We reviewed patients with IPF who were admitted between January 2008 and December 2014 for pulmonary infections including pneumonia and bronchitis. The causative pathogen, the relationship between the site of pneumonia and existing IPF radiological patterns on high-resolution chest CT, and predictors of mortality were evaluated. Forty-eight IPF patients were hospitalized a totally of 81 times due to pulmonary infection during the study period. In the 48 first-time admissions after IPF diagnosis, causative pathogens were detected in 20 patients (41.6%). The most common pathogen was Haemophilus influenzae (14.5%) followed by Pseudomonas aeruginosa (4.1%), Staphylococcus aureus (4.1%), Branhamella catarrhalis (4.1%), and Klebsiella pneumoniae (4.1%). Among all 81 admissions, the most common pathogen was P. aeruginosa (12.3%), followed by H. influenzae (8.6%), S. aureus (6.1%) and Escherichia coli (4.9%). No relationship was observed between the detected pathogen and the site of pneumonia. The 30-day and hospital mortality rates were 14.5% and 18.7%, respectively. Pneumonia severity index on admission was significantly associated with both 30-day and hospital mortality. In conclusion, IPF patients hospitalized for pulmonary infections had high 30-day and hospital mortality. In contrast to community-acquired pneumonia, the causative pathogens mainly consisted of gram-negative bacteria. The PSI score may be a significant predictor of mortality. These results provide information for empiric antibiotic selection when treating IPF patients with pulmonary infections.

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and ß2-Adrenoceptor Agonists in Airway Smooth Muscle.

Long-acting muscarinic antagonists (LAMAs) and short-acting ß2-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 µM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K⁺ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between ß2-adrenoceptors and muscarinic receptors.

Pulmonary Hemodynamics and Six-Minute Walk Test Outcomes in Patients with Interstitial Lung Disease.

Background. Six-minute walk test (6MWT) has 3 measurement outcomes, which are walk distance, desaturation, and symptom. The aim of this study was to examine whether routinely measured right-heart catheter (RHC) data correlate with 6MWT outcomes in patients with interstitial lung disease (ILD). Methods. Between June 2010 and December 2012, consecutive patients with ILD who underwent evaluation, including pulmonary function test, hemodynamic studies with right-heart catheter, and 6MWT as routine general practice, were recruited. Correlates of 3 outcomes of 6MWT were examined to reveal significant predictors. Results. Forty-six patients consisting of 20 with idiopathic pulmonary fibrosis, 14 with collagen vascular disease associated ILD, and 12 with other idiopathic interstitial pneumonia were recruited (mean % predicted FVC: 76.7 ± 17.1%). Several physiological variables, including mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), were correlated with each 6MWT outcome. Stepwise multivariate regression analyses showed that % predicted FVC and % predicted DLco were independent predictors of walk distance (r (2) = 0.35, p = 0.0002). For SpO2 at the end of 6MWT, % predicted DLco and PVR were selected as independent predictors (r (2) = 0.46, p < 0.0001). For dyspnea at the end of 6MWT, % predicted DLco was only one predictor (r (2) = 0.18, p = 0.005). Conclusion. Mean PAP had little impact on 6MWT outcomes in ILD patients who were nonselectively recruited, although PVR was one of predictors of desaturation.

[Role of bronchodilators in therapy for COPD-mechanisms of LABA and LAMA on airway smooth muscle].

Long-acting ß2-adrenergic receptor agonists (LABAs) and anticholinergics (LAMAs) are widely used clinically as therpy for COPD. Clinical reports have demonstrated that LABAs (salmeterol, formoterol, indacaterol, olodaterol, vilanterol) and LAMAs (tiotropium, glycopyrronium, umeclidinium, aclidinium) are useful to improving symptoms and lung function, and to reducing exacerbation and hospitarization. LABAs expect salmeterol are strong partial agonists, and LAMAs are non-specific antagonists. Ca2+ dynamics and Ca2+ sensitization contribute to relaxation of airway smooth muscle in these bronchodilators. LABAs act on orthosteric and allosteric sites on the ß2-adrenergic receptors. In contrast, LAMAs act not only on orthosteric site on the muscarinic receptors, but also allosteric site on the ß2-adrenergic receptors, leading to enhancing ß2-adrenergic action. Allosteric GPCR modulation is involved in the synergistic effects between LABAs and LAMAs.

Prognostic value of forced expiratory volume in 1 second/forced vital capacity in idiopathic pulmonary fibrosis.

Emphysema on high-resolution computed tomography of the chest is the recent focus in the general practice in idiopathic pulmonary fibrosis (IPF). However, adequate attention has not been paid to obstructive disorder. Therefore, we retrospectively evaluated the association between the degree of airway obstruction and longevity in IPF subjects, with a hypothesis that lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) has an impact on prognosis. One hundred and fourteen consecutive IPF subjects who had been diagnosed with IPF and had undergone evaluation including pulmonary function test from January 2008 to May 2013 were included in the study. The relationship between baseline data and survival was examined. FEV1/FVC was widely distributed, ranging from 48.6% to 100%. On both univariate and multivariate Cox's regression analyses, lower FEV1/FVC was significantly associated with better survival (hazard ratio of 1.07 and 1.04 and 95% confidential interval of 1.03-1.10 and 1.01-1.08, respectively). Even on analysis with backward selection, FEV1/FVC remained a significant prognostic factor. FEV1/FVC is widely distributed and negatively predicts survival in IPF. A FEV1/FVC should be assessed in "real-world" general practice. Also, the effect of smoking on the clinical course of IPF should be investigated further.

Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and ß2-adrenergic intrinsic efficacy.

Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and ß2-adrenergic receptor activity. Large-conductance Ca(2+)-activated K(+) (KCa) channels are activated by ß2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca(2+) influx passing through voltage-dependent Ca(2+) (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of ß2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between ß2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of ß2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between ß2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes ß2-adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of ß2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling.