Day 2 :
Kindai University, Japan
Keynote: Involvement of allosteric GPCR modulation in synergistic effects of beta-adrenergic receptor agonists with muscarinic receptor antagonists in airway smooth muscle
Time : 09:05-09:50
Hiroaki Kume obtained his MD from Toyama Medical and Pharmaceutical University in 1982. He has completed his PhD in Department of Medicine (II), Nagoya University School of Medicine in 1990, and postdoctoral studies from School of Veterinary Medicine, University of Pennsylvania (Dr. Michael I. Kotlikoff’s Lab). Currently, he works at Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, and focuses on investigating the characteristics of airway smooth muscle using physiological methods, with the goal of identifying therapeutic targets for asthma and COPD.
Rationale: Long acting b2-adrenergic receptor agonists (LABAs) and muscarinic receptor antagonists (LAMAs), are used as bronchodilators to improve lung function, symptoms, and QOL in COPD. Since these agents may cause a desirable cross talk between b2-adrenergic and muscarinic receptors, combination of LABA with LAMA has pharmacological rationale as a bronchodilator therapy. This study was designed to determine mechanisms underlying synergistic interaction between these agents with a focus on allosteric modulation.
Methods: For record of isometric tension, the strips of tracheal smooth muscle of guinea pigs were placed in the organ bath and were perfused with the physiological solution. The responses to an agent under each condition were described as a percentage of the maximal response. Allosteric modulation was analyzed using concentration-inhibition curves.
Results: 1 nM tiotropium, LAMA, caused a modest inhibition (5.6%, n = 8) of 10 mM MCh-induced contraction. Relaxant action of 0.3 nM formoterol, LABA, was increased from 12.1 to 35.8 percent inhibition (P<0.01) in the presence of tiotropium (1 nM). When formoterol was cumulatively applied to the tissues pre contracted by 10 mM MCh, EC50 was 1.8 nM, and the maximal inhibition was 68.9% (intrinsic efficacy). In the presence of 1 nM tiotropium, concentration-inhibition curves for formoterol was shifted to the left, and moved to upper side. EC50 was decreased to 0.3 nM (P<0.05), and maximal inhibition was augmented to 92.4% (P<0.01).
Conclusions: Tiotropium synergistically enhances formoterol-induced relaxation against muscarinic contraction in airway smooth muscle. Since tiotropium reduces the EC50 and elevates the maximal inhibition in the concentration-inhibition curves for formoterol against MCh, tiotropium binds to allosteric sites on b2-adrenergic receptors, leading to enhancements of affinity and efficacy to formoterol via allosteric modulation. Therefore, allosteric modulation contributes to synergistic effects between LAMA and LABA, and combination of these agents may be beneficial to therapy for COPD.
- CO-Morbidities in COPD | Self-Management and Prevention of COPD
Yeungnam University Hospital, South Korea
Mi Suk Lee
Yeungnam Univ. Hospital, South Korea
Yeungnam University Hospital, South Korea
Dr. Kyeong-Soo Lee is the Head of the Preventive Services Center at the Regional Center for Respiratory Disease, Yeungnam University Hospital. His major is preventive medicine, and he has extensive experience in community health work and professional workforce training. Since 2008, he has been involved in community health survey(CHS) in Korea and has participated in research and projects to promote health promotion, chronic diseases, and infectious diseases at the national or local government level.
Statement of the Problem: Tuberculosis is the disease with the highest incidence and mortality rate among the statutory infectious diseases administered by the state. In Korea, the incidence of tuberculosis increases after 15 years. Students live in the same space and have greater opportunities for exposure because they are more active. Prevention of tuberculosis in schools and prevention of tuberculosis suspected or confirmed cases should be prevented early. In order to prevent effective tuberculosis and prevent the spread of infection, Yeungnam University Hospital and Daegu Metropolitan City jointly produced and distributed 'Manual for School Tuberculosis Response' for middle and high school students.
Methodology & Theoretical Orientation: Daegu Metropolitan City and Yeungnam University Hospital Regional Center for Respiratory Disease for the prevention and management of students. Based on the "National Tuberculosis Control Guideline" issued by the Ministry of Health and Welfare of Korea, and also it was prepared in accordance with the situation of Daegu Metropolitan City. We held nine meetings and two workshops in 2015 to build the manual. Experts from Daegu Metropolitan City Office, Public Health Center, Ministry of Education, and participating medical institutions participating in the PPM national TB project jointly participated.
Findings: This manual contains information on the status of tuberculosis in Daegu Metropolitan City, the stage of preparation for tuberculosis, the response and measures in case of suspected tuberculosis or tuberculosis, and the role of related organizations. In addition, Q & A method is presented for cases of school tuberculosis confirmed cases and how to respond to situations. The manual was distributed to 227 middle and high schools and 24 related institutions in Daegu Metropolitan City and the manual was released on the website of Daegu Metropolitan Office of Education (www.dge.go.kr) so that it can be used in schools.
Conclusion & Significance: It is meaningful that this manual was developed and distributed in accordance with the situation of middle and high schools in Daegu Metropolitan City.
Schoen Klinik Berchtesgadener Land, Germany
Vasileios Andrianopoulos is a clinical exercise physiologist working as postdoctoral research fellow at Schoen Klinik Berchtesgadener Land in Germany. He has his expertise in COPD pathophysiology, clinical exercise assessment and Pulmonary Rehabilitation programs for COPD patients. Devoting himself to research, he acquired experience in designing research protocols, analyzing data and writing manuscripts as well as in operating several clinical devices. He has numerous publications in healthy and patients with COPD and since 2014 is an active member of the European Respiratory Society (ERS) College of Experts. Recently (2016), he has been awarded with a prestigious Marie Skłodowska-Curie fellowship cofounded by the European Union and the European Respiratory Society (ERS) for his project about cognitive dysfunction in COPD.
Background: Cognitive impairment (CI) is a prevalent extrapulmonary manifestation in COPD. Potential disturbances in cerebral circulation and oxygen delivery due to reduced ventilatory efficiency and ventilatory drive may be associated with higher rates of CI.We assessed cerebral tissue oxygen index (TOI) and cerebral hemodynamics at exertion in COPD patient with and without CI.
Method: 52 COPD patients (aged: 68±8yrs; FEV1: 45±14%; 40%women) underwent a comprehensive cognitive assessment. Patients were assigned to “CI” and “non-CI” groups according to Montreal Cognitive Assessment (MoCA) cutoff score ≤25points. Patients performed cycle endurance test (CET) at 75% of peak work rate while transcutaneous carbon-dioxide partial-pressure (TCPCO2), cerebral tissue oxygen index (TOI) and cerebral hemoglobin responses were recorded by SenTec and Portalite systems, respectively.
Results: 23 patients (44%) presented evidences of CI (MoCA≤25) with also lower scores in other cognitive tests (all p <0.001). A correlation between TCPCO2 and cerebral oxygenated hemoglobin (O2Hb), and total hemoglobin (tHb) at the end of CET was detected (r: 0.34, p=0.021; r: 0.34 p=0.023, respectively). Oxygen saturation (SpO2) at the end of CET was not related with cerebral deoxygenated hemoglobin (HHb) and tHb. Patient with CI developed similar cerebral hemodynamic pattern and TOI compared to non-CI during CET.
Conclusion: COPD patients have the capacity to autoregulate cerebral cortex blood flow in response to hypercapnia and hypoxemia, at least during exercise, and thus to normalize cerebral tissue oxygenation. These findings suggest that exercise is safe and can be beneficial regarding to cognitive function in COPD.
The Chinese University of Hong Kong, Hong Kong
Dr. Doris Leung, (PhD), now is an Assistant professor at the Netherosle School of Nursing, The Chinese University of Hong Kong. She got hers B Sc in and MPhil in Statistics at The Chinese University of Hong Kong and PhD in Biostatistics at University of California, Los Angeles. Her main interests are in educational and health psychology and scale validation. She has co-authored more than 120 papers/abstracts published in peer-reviewed journals and generated over 150 conference abstracts. She also served on editorial board and invited reviewers in several international journals. Her current research programs include cancer prevention, chronic disease management, palliative care and teaching and learning in higher education.
Background: Self-management has been used for decades as a means to tackle the challenges of chronic obstructive pulmonary disease (COPD). A recent systematic review concluded that interventions promoting self-management among COPD patients were effective in improving patients’ health outcomes, yet the most effective component of these interventions remains elusive. A better understanding of the underlying phenomenon of how COPD patients engage in self-management behaviors is urgently needed. The purpose of this study is to test the goodness-of-fit of an evidence-based theoretical model to explain the factors that affect self-management behaviors in COPD patients.
Methods: A cross-sectional study employing a convenience sampling was conducted. Adult COPD patients were recruited when they had their follow-up visits in six clinics. Structural equation modeling used to test the goodness-of-fit of the hypothesized model utilizing the EQS software. Model modifications were made based on theoretical plausibility and statistical significance.
Results: The findings revealed that ten factors exerted significant total effects on self-management behaviors: eight of them had positive effects while two had negative effects. Among these significant factors, physical limitation had the greatest positive total effect on self-management behaviors, but the direction of the effect was contradicted to expectation. A further analysis on the relationships of self-management behaviors with functional limitations, dyspnea and fatigue suggested inverted U-shape non-linear relationships. Conclusion: This newly developed evidence-based theoretical model provides insight into the understanding of the complex phenomenon of COPD patients’ engagement in self-management behaviors which could be used to guide the development of interventions to promote self-management behaviors in COPD patients.
Recommendations: Future study could replicate the current study and cross-validate the evidenced-based theoretical model using a larger population of COPD patients with different ethnic origins, in particular, the non-linear relationship with severity of the disease.
D.Margaretha Lundin has her expertise in social work and passion in improving the health and wellbeing. She has built this patient education together with her team which includes a doctor, a registered nurse, an urotherapist, a dietician, a dental hygenist, a hospital librarian, an occupational therapist, an enrolled nurse, a physical therapist and a speech therapist. During the process, a group of COPD patients, their relatives and The Swedish Heart and Lung Association were also involved in the process.
Statement of the problem: The primary cause of Chronic Obstructive Pulmonary Disease (COPD) is tobacco smoking. Who predicts that COPD will become the third leading cause of death worldwide by the year of 2030.
Pulmonary rehabilitation based on self-management is an evidence-based, multidisciplinary and cost-effective intervention that leads to improved health in patients with COPD. However, in Sweden only 42 % of all COPD patients in specialist care participate in self-management education initiatives.
Purpose/Methods: This project aims to help more COPD patients to improve their self-management capabilities. We invite patients and their relatives to iterative and interactive training sessions supported by digital tools. The content and process of the education including the digitalized tools have been co-designed by patients in collaboration with a cross-professional COPD-team.
Conclusions: The prevalence of COPD is continuously increasing thus putting more pressure on health care delivery. Self-management is an underused but powerful approach for improved care of the disease.
Using COPD education together with new technology we provide COPD patients and their relatives with tools for improved self-managed care thus empowering patients even more. Previous experiences have shown that knowledgeable patients make better choices that also promote health
Albany Medical College, USA
Dr. Yong-Xiao Wang has been a Full Professor in Albany Medical College (USA) since 2006. Dr. Wang has had extensive research experience in basic, translational and drug research concerning pulmonary hypertension, asthma, chronic obstructive pulmonary disease, diabetes, and cardiac arrhythmia for over 30 years. As the Principal Investigator, he has/had numerous NIH R01 research awards, AHA Established Investigator Award, and various other grants, for which he often holds/held 2 – 3 NIH R01 grants with other awards each year. As the corresponding author, first author and key contributor, he has had numerous publications in highly peer-reviewed journals including Antioxid Redox Signal (impact factor: 8.209), Proc Natl Acad Sci USA (9.432), Nature (34.480), Circ Res (9.214), etc. Dr. Wang has been the editor of academic books in the field including one entitled by “Redox Signaling in Health and Disease Pulmonary Vasculature” that has been confirmed for publication by Springer (New York).
Statement of the Problem: Pulmonary hypertension is a common devastating lung disease. It is a primary cause of death in chronic obstructive pulmonary disease (COPD) and numerous other cardiovascular and respiratory disorders. COPD is currently the fourth leading cause of mortality and may become the second leading cause of death by 2020. Currently, no specific and effective drugs are available to treat pulmonary hypertension, and the underlying molecular mechanisms are not well understood.
Purposes: The current research project was to test a novel hypothesis that the reciprocal crosstalks between ion channel-mediated calcium signaling and transcriptional factor-dependent inflammatory signaling are essential for COPD. The current study also sought to determine whether specific genetic and pharmacological targets for these signaling molecules would become effective therapeutics for COPD.
Methodology: Pulmonary artery vasoconstriction, remodeling and hypertension were, respectively, examined using in-situ immunohistological staining, and organ bath technique, and pressure-volume loop method; activity and Ca2+ release of ryanodine receptor/Ca2+ release channel (RyR) were determined using [3H]-ryanodine binding assay and fluorescence imaging; specific gene knockout (KO) mice were generated using standard methods, and association of RyR2 with FK506 binding protein with a molecular weight of 12.6 kDa (FKBP12.6) was determined by assessing RyR2/FKBP12.6 protein ratio using co-immunoprecipitation.
Findings: Like COPD, hypoxic exposure causes significant pulmonary artery vasoconstriction and remodeling in mice, leading to pulmonary hypertension. The activity of RyR Ca2+ release channel is largely enhanced in pulmonary artery smooth muscle cells (PASMCs) from mice with pulmonary hypertension. RyR-mediated Ca2+ release is also augmented as well. Specific RyR2 channel KO abolishes hypoxia-induced pulmonary artery vasoconstriction, remodeling and hypertension. RyR2 KO also completely inhibits the enhanced RyR activity and function (Ca2+ release) in PASMCs of mice with pulmonary hypertension. Subcutaneous administration of tetracaine, a pharmacological RyR blocker, blocks hypoxia-evoked pulmonary artery vasoconstriction, remodeling and hypertension in mice as well. RyR Ca2+ release channel is physiologically associated with FKBP12.6 and thus shows a low activity. RyR2/FKBP12.6 association is significantly diminished in PASMCs of mice with pulmonary hypertension. Specific FKBP12.6 KO promotes hypoxic pulmonary artery vasoconstriction, remodeling and hypertension. Treatment with S107, a RyR2/FKBP12.6 association stabilizer, produces opposite effects.
Conclusion & Significance: RyR2/FKBP12.6 complex is a primary target for pulmonary hypertension, and RyR2 channel blocker and FKBP12.6 stabilizer may become novel and effective drugs in treatment of this disease.