Title : Emerging prospective on molecular pathogenesis and therapeutic targets for COPD
Chronic obstructive Pulmonary Disease (COPD) is a devastating common lung disease. It is the third leading cause of mortality in the world and will be the second leading cause of death by 2020. The current challenging tasks are that the molecular mechanisms for COPD remain largely unknown, and clinical therapeutic options are limited. A major characteristic of COPD is expiratory airflow limitation, which can be attributed to airway hyperresponsiveness and remodeling. We and other well-known scientists have unveiled that a very important player (VIP) in these two major cellular responses is an increase in intracellular calcium ([Ca2+]i) in airway smooth muscle cells (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 is associated with their inhibition of the increased [Ca2+]i in ASMCs. Recent studies from our group and others suggest that multiple ion channels, particularly 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 in ASMCs and thus are essential for airway hyperresponsiveness and remodeling in COPD and/or 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/or remodeling in COPD. We have further revealed that ROS are primarily produced by mitochondria and NADPH oxidase (NOX), but mitochondria are the primary site. Several 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 roles in COPD by causing of oxidation of IP3R, RyR, and TRPC3 channels, leading to their hyperfunctions. We and other eminent investigators have further provided new evidence that virus-mediated shRNA-based genetic (specific) inhibition and highly selective pharmacological inhibitor of these channels may become more effective therapies for COPD.