Day 1 :
Albany Medical College, USA
Keynote: Promising molecular mechanisms and therapeutic options for chronic obstructive pulmonary disease (COPD)
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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 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 was published by Springer (New York) last fall. Dr. Wang has also served as the editorial board member and/or section editor for the Clinical and Translational Medicine, Pulmonary Circulation and several other journals.
COPD is the third leading cause of mortality in the world and will be the second leading cause of death by 2020. However, the molecular mechanisms for this devastating disease remain largely unknown; currently, the clinical therapeutic options are neither specific and nor always effective. A major characteristic of COPD is expiratory airflow limitation, which can be attributed to airway hyperresponsiveness. A very important player (VIP) in airway hyperresponsiveness is the increased contraction of airway smooth muscle cells (ASMCs). An increase in intracellular calcium ([Ca2+]i) is a key factor in the increased contraction in AMCs. Consistent with this view, bronchodilators including muscarinic receptor antagonists, β-adrenergic receptor agonists and corticosteroids are used as the first-line drugs in the clinical treatment of COPD, and the functional role of all these forefront drugs are associated with their inhibition of the increased [Ca2+]i and contraction in ASMCs. Multiple ion channels such as inositol trisphosphate receptor (IP3R)/Ca2+ release channel, ryanodine receptor (RyR)/Ca2+ release channel and canonical transient receptor potential-3 (TRPC3) channel, play a major role in initiation and maintenance of [Ca2+]i. Recent studies suggest that these channels are essential for airway hyperresponsiveness in COPD and other pulmonary diseases. Equally interestingly, IP3R, RyR and TRPC3 channels are highly sensitive to reactive oxygen species (ROS), and ROS are well known to mediate airway hyperresponsiveness and other unleashed cellular responses in COPD. ROS are primarily produced by mitochondria and NADPH oxidase (NOX). A number of antioxidants targeted at mitochondria and/or NOX are currently used in clinical trials and show potential effectiveness in the treatment of COPD. ROS may implement their role in COPD by causing of oxidation of IP3R, RyR and TRPC3 channels, leading to their hyperfunctions. Thus, it is reasonably believed that genetic and pharmacological inhibition of these channels, like antioxidants, may also be effective for therapies of COPD. In support, studies using animals have revealed their therapeutic for airway hyperresponsiveness and COPD.
University of Virginia
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Kun Qing is an MR scientist with more than nine years of experience working in the medical imaging research field. Currently, I am serving as an Assistant Professor of Radiology & Medical Imaging at University of Virginia (UVa). My research has primarily focused on development and optimization of MR and image processing techniques to provide better depiction of lung structure and function. Also I served as PI or Co-Investigator on multiple research projects and performed MR imaging studies to investigate patients with pulmonary diseases and their responses to treatments. The hyperpolarized xenon-129 dissolved-phase MRI [ref 1] that I developed is the first non-invasive imaging technique to measure regional gas exchange in the human lung. It showed its unique abilities to characterize lung disease and detect early changes of lung function in many primary lung diseases.
Purpose: Airway-predominant chronic bronchitis (CB) and alveolar-predominant emphysema (EM) were regarded as major phenotypes of smoke-induced COPD. Routine clinical tools, including pulmonary function tests (PFTs) and computed tomography (CT), have their limitations to characterize COPD. This study will characterize COPD phenotypes using a new imaging tool - hyperpolarized xenon-129 (Xe129) MRI .
Methods: Thirteen healthy and thirty-three COPD subjects were recruited and underwent PFT, CT. COPD patients were phenotyped into three groups by PFT percent diffusion capacity (%DLCO) and CT percent of EM lung tissue (%EM): 1) EM: low %DLCO and high %EM; 2) CB: high %DLCO and low %EM; and 3) mixed indeterminate (IND) phenotype: low %DLCO but low %EM. Xe129 MRI was subsequently administered to determine airflow limitation by measuring percent of ventilation dead space (%VD) and alveolar gas uptake by measuring Xe129 diffused into interstitial tissue [tissue/gas ratio, reflecting lung tissue integrity] or into red blood cells (RBCs) [RBC/tissue ratio, reflecting gas exchange and pulmonary perfusion].
Results and Discussion: Using the criteria described above, 18% of patients (6/33) were EM predominant; 21% (7/33) were CB phenotype; and surprisingly, 61% (20/33) were IND phenotype. The IND group had %FEV1 substantially overlapped the CB group (p>0.05, Figure 1a), and did not show significantly higher %VD than the control group (p>0.05, Figure 1b). Also, no statistical differences were found in Xe129 tissue/gas ratios among the control, CB and the IND groups (p>0.05). However, the RBC/tissue ratios, measuring gas transfer from the interstitium further to the blood stream, were much lower in the mixed group as compared to all other groups (p<0.05) (Figure 1d).
Conclusion: There seemed to be a new mixed phenotype of COPD identified in a majority of COPD patients, which had minimal emphysematous tissue destruction, but impaired gas exchange to the blood as indicated by Xe129 MRI.