Project 143 – Epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): role in both airway fibrosis and lung cancer

28 Jan 2016

Dr Sukhwinder Sohal – $43,127

Smoking related COPD imposes a huge cost on the Tasmanian community, where smoking rates are the highest in the country. The most recently available data show that between 2003 and 2007, an average of 568 Tasmanians died each year due to tobacco use.

We need better detailed understanding of COPD pathogenesis, in order to design better translational treatments. Tobacco smoke is a major etiological factor for COPD. However, only 25% of smokers will develop ‘classic’ COPD, in these vulnerable individuals the progression of airways disease to symptomatic COPD occurs over two or more decades. Detailed data on airway structural changes in COPD are especially sparse, and how these changes lead to airway fibrosis and lung cancer are poorly understood.This project aims to build up a respiratory tissue bank for the first time in the North of the state by collecting samples from all COPD patients at the LGH. The aim is then to assess the mechanisms driving highly plastic changes associated with airway cells (EMT) and effects of drugs on these changes. This will have huge therapeutic implications for both airway fibrosis and lung cancer which are very common in COPD.

The project found that Empirically, the basic pathophysiological abnormality that develops in smokers is small airway fibrosis causing narrowing and destruction, with a broader bronchitis (inflammation) throughout the airways. Although inflammation in smokers and COPD seems to be more a luminal phenomenon rather than being associated to airway wall. The other main airway pathology in COPD is lung cancer; up to 50% of smoking related lung cancer occurs in mild-moderate COPD or early disease. It is becoming likely from this work that epithelial plasticity or epithelial mesenchymal transition (EMT) underlie these nasty pathological features. During the process of EMT, the cells lining the breathing tubes in the lung become fibrotic or cancer associated. They change their phenotype in response to persistent outside insult (smoking). We found that this cell plasticity responds to clinically prescribed drugs as well, such as inhaled corticosteroids. These observations open up major new therapeutic possibilities. This work enhances our understanding on these mechanisms and how we can potentially switch them off. Other major strength is that all of our research work is done in human clinical setting, which directly leads to better management of patients.

Through this project, we have also been able to build up a respiratory tissue bank for the first time in the North of the State by collecting clinical samples from smokers and COPD patients at Launceston General Hospital (LGH) and recruitment is still ongoing as part of the future projects. We are very thankful to the Respiratory Physicians at LGH for their kind support into this. Unfortunately, the research effort into COPD has been disproportionately very weak compared to its social importance. Only 25% of smokers will develop “classic” COPD. We do not know why only a minority deteriorate in this way, or why only these individuals are disproportionally susceptible to lung cancer. A better understanding may lead to new clinical markers for incipient neoplasia, and better preventive management of COPD patients. Our finding that EMT expression increases in smokers and COPD current smokers may help to understand why lung cancer is so common in smokers, and indeed, why it is so aggressive, invasive and fatal in over 85% of cases. Tobacco smoking is the major aetiological factor for COPD in developed countries, but the links between COPD and clinical outcomes are poorly understood. Smoking related COPD imposes a huge cost on the Tasmanian health care system, where smoking rates are the highest in the country. Therefore, we need a better-detailed understanding of COPD pathogenesis, in order to design better translational treatments.