Role of Oxidative and Nitrative Stress and Histone De-acetylation in Rhinovirus Induced Acute Exacerbations of COPD

Chronic obstructive pulmonary disease (COPD) or smokers? lung is a growing problem and already one of the commonest causes of death and disability in the UK. COPD accounts for over #800 million in direct healthcare costs. Seventy percent of these costs are related to acute attacks. Acute attacks are also dreaded by COPD sufferers, as they lead to severe breathlessness, prolonged hospitalisation or death. Current therapies are not good at either treatment or prevention of acute attacks. New approaches to therapy are therefore urgently needed. COPD is associated with inflammation in the lung, which gets worse as the disease progresses. Acute attacks also involve inflammation in the lung but how this occurs is very poorly understood. Most acute attacks are caused by common cold viruses, which ?go to the chest?. We plan to carry out detailed studies of virus induced acute attacks of COPD, to understand the molecules switching on inflammation in the lung during these attacks. By identifying the molecules that increase lung inflammation during these attacks, we should be able to identify targets for the development of new therapies for both prevention and treatment of acute attack of COPD. So doing would greatly reduce distress suffered by COPD patients, as well as reducing mortality and health care costs.

Respiratory viral infections are detected in 40-60% of exacerbations of COPD and 2/3 of patients report common cold symptoms preceding exacerbation. Rhinoviruses (RV) are the major virus type identified. Existing treatments are poorly effective at treating or preventing COPD exacerbations. New treatments are urgently required to reduce the associated morbidity, mortality and health care costs. To identify targets for the development of new treatments, understanding of the molecular mechanisms of COPD exacerbations is required.
Inflammatory gene transcription is up-regulated by acetylation and down-regulated by deactylation of histones. Stable COPD is associated with increased oxidative/nitrative stress, degradation of histone deacetylase-2 (HDAC2), transcription factor activation, resulting in airway inflammation. Rhinovirus infection of epithelial cells rapidly induces oxidative stress and inflammatory gene transcription.
We hypothesize that (i) RV infection of epithelial cells and macrophages in vitro induces oxidative/nitrative stress leading to nitration of HDAC2 and its degradation - this results in increased acetylation of histones and of specific transcription factors leading to enhanced inflammatory gene transcription (ii) these pathways are all up-regulated in COPD patients compared to control subjects on RV infection in vivo and are related to increased airway inflammation, virus load, respiratory symptoms and reductions in lung function.
RV experimental infection in asthma provides a model of virus-induced asthma exacerbations allowing investigation under controlled conditions of the molecular mechanisms of asthma exacerbations. We have developed an experimental RV infection model in moderate COPD patients and have shown it is safe and induces lower respiratory symptoms and reductions in lung function typical of COPD exacerbations.
We propose an experimental infection study in moderate COPD patients and age/smoking matched non-obstructed control volunteers to investigate the molecular mechanisms of COPD exacerbations with the aim of identifying targets for the development of new therapies. Lower respiratory tract sampling will be carried out at baseline, intensively during exacerbation, through recovery and at 6 weeks. These in vivo studies will be complemented by in vitro studies investigating molecular mechanisms of RV induction of inflammation in bronchial epithelial cells and macrophages. Molecular targets identified by the in vitro studies will then be confirmed and related to airway inflammation, virus load, respiratory symtpoms and lung function in vivo. Finally we will investigate pharmacologic/genetic inhibition of key regulatory molecules in vitro to identify novel targets for development of new therapies for acute exacerbations of COPD.