Abstract
Yong-Xiao Wang
Abstract
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. Although longacting bronchodilators were an significant advance in chronic obstructive pulmonary disease (COPD) treatment, these drugs do not deal with the underlying inflammatory cycle. No therapies currently available reduce COPD development or suppress the inflammation in the narrow airways and lung parenchyma.Several new therapies that target the inflammatory process are currently under clinical development. Many therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma occurring in COPD while others are targeted at inflammatory cytokines such as tumor necrosis factorα.Broad spectrum antiinflammatory drugs are currently under development for COPD in phase III, and include inhibitors of phosphodiesterase.Other drugs that inhibit cell signalling include p38 mitogenactivated protein kinase inhibitors, nuclear factorÿB, and phosphoinositide-3 kinase π. More specific approaches are to provide antioxidants, inducible nitric oxide synthase inhibitors and B4 antago leukotriene.Certain drugs have the ability to counter mucus hypersecretion, and serine proteinase and matrix metalloproteinase inhibitors are also being pursued to prevent lung damage and emphysema production. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.Current chronic obstructive pulmonary disease (COPD) therapy has improved the management of this difficult disease, but new therapeutic approaches are still urgently needed, especially in reducing the progression and mortality of this disease. COPD has now become amuch greater drain on health services than asthma, and exceeds health spending on asthma bysome threefold.As COPD prevalence is predicted to increase worldwide over the next 20 yrs these costs will further escalate. There is no doubt that COPD management has significantly improved with more effective treatments and the use of nonpharmacological interventions, such as pulmonary rehabilitation and noninvasive ventilation (NIV).The development of new therapies for COPD is urgently needed , particularly since no existing treatment has been shown to reduce the progression of the disease. New therapies for COPD may result from improvements in existing drug classes or new therapies based on a better understanding of the underlying disease.Significant advances have been made in the current understanding of COPD's cellular and molecular biology and this was previously reviewed 3. There are now several new COPD therapies in development that are geared to the chronic inflammatory process. This study addresses some of those therapies. Clearly there is a need for further research into the central mechanisms of COPD, and although the inflammatory cycle is now much better understood, it is not yet clear that inflammation suppression can stabilize COPD.The inflammatory cycle is thought to contribute to these systemic changes, and is thus the scientific basis for the production of antiinflammatory therapies. It is possible, however, that the structural changes can develop independently of the inflammation and that dysregulated repair mechanismscan even drive the inflammatory process, a concept now emerging in fibrotic lung diseases. There are several reasons why it is difficult to develop drugs within COPD. COPD animal models are not very satisfactory for early drug testing. There are uncertainties about how to test COPD drugs in relatively large numbers of patients, which may require longterm studies (over 3 yrs). Many COPD patients may have co-morbidities, such as ischaemic heart disease and diabetes, which could exclude them from new therapy clinical trials. Few information is available on surrogate markers (e.g. biomarkers in blood, sputum, or breath) to track short-term efficacy and assess the long term potential of new therapies.Cigarette smoking is the world's leading cause of COPD and smoking cessation is the only therapeutic intervention that has been shown to reduce disease progression so far. Nicotine addiction / dependency is the main problem and this addictive state should be addressed in the treatment.Several forms of nicotine replacement therapy and other antidepressant medications are currently being used, but the efficacy of these therapies is poor and only a minority of patients sustain abstinence for 6 months.Atypical antidepressant bupropion is the most effective therapy available and a short course is an effective adjunct for smoking cessation in COPD patients. 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.