Scientists: David Holdsworth, PhD, Giles Santyr, PhD, Grace Parraga, PhD & Maria Drangova, PhD
Lung diseases including asthma and chronic obstructive pulmonary disease (COPD) remain the 3rd leading cause of death in Canada, and each year over 12,000 Canadians will succumb to lung diseases and disorders. For COPD alone, the cost of treatment, rehabilitation, loss of productivity from disability, and premature death totals $80 billion a year. The Lung Imaging Research Program at Robarts strives to provide new ways to predict, prevent, and manage lung diseases, and to provide new tools for the development of better treatments. The program is strengthened by collaborations with other leading lung research centres in Canada and the US. The respiratory imaging research team has developed innovative in vivo magnetic resonance imaging (MRI) and computed tomography (CT) approaches to study patients with respiratory disease including asthma as well as small animal models of lung disease. They were the first lab in the world to successfully demonstrate high field hyperpolarized 3He MRI of COPD and asthma as well as quantitative ventilation phenotypes in COPD and healthy age-matched elderly volunteers. It was also shown that imaging measurements could be used to categorize COPD patients independent of pulmonary function measurements. Recently, the first xenon-enhanced CT images of rodent lungs were achieved by the team, adding functional understanding to anatomical information.
Asthma is a chronic inflammatory disease of the lungs and is typically diagnosed and characterized by the measurement of airflow obstruction using spirometry. It continues to remain an important clinical problem in Canada – both from a patient management point of view and in terms of resource allocation. Analysis of acute attack asthmatic lungs suggests there is a wide distribution of airway and airspace changes. In the team's preliminary study of exercise-induced asthma (EIA) they were surprised to observe significant persistent lung functional changes that were variably increased during EIA. The overarching goal for this research is to identify new imaging measurements of disease to evaluate new treatments and response to treatment in children and adults.
Cystic fibrosis is characterized by the presence of increased airway mucus associated with mutations in the cystic fibrosis transmembrane conductance regulator gene. The inability of the lung to effectively clear the abnormal mucus results in chronic lung infection and is the dominant risk factor for increased illness and early death. Despite decades of research into the genetic, molecular, physiological, and cellular aspects of CF, new treatment improvements over the last 10 years have focused only on secondary approaches, including a class of treatments that promote mucus degradation and clearance. However the response to these (often expensive) therapies is both variable and unpredictable. One potential cause of the variable response to treatment (which is so far untested) is the regional heterogeneity of the disease. The respiratory team's goal for CF research is to identify new measurements of the disease that can be used in clinical trials of new treatments including localized stem cell and genetic therapies.
Chronic Obstructive Pulmonary Disease and Emphysema
The development of chronic lung disease related to tobacco smoking, the use of biomass fuels, and inhalation of environmental toxins, known as Chronic Obstructive Pulmonary Disease (COPD) affects at least one million Canadians and 700 million people globally. It is currently the fourth leading cause of death worldwide and continues to grow in prevalence and mortality rates. It is directly responsible for 100,000 hospitalizations and 10,000 deaths each year in Canada, costing over $5 billion in direct and indirect costs. Despite the staggering societal burden of COPD and decades of active research, therapeutic breakthroughs have not occurred, largely because there is: 1) an incomplete understanding of the disease, 2) inadequate methods to differentiate underlying disease subtypes, and, 3) a scarcity of tools that can sensitively and precisely track disease changes. In response to these serious limitations, non-invasive in vivo imaging techniques have been proposed as promising solutions because of their potential to provide new remedial intermediate markers or phenotypes that directly quantify lung pathologic and functional changes. The focus of the team's research is the quantification and validation of such in vivo COPD phenotypes. Preliminary studies suggest that 3He MRI may be ideally suited for longitudinal clinical research of COPD, which is a likely target application of this novel technology. 3He MRI may provide a complementary and alternative method for evaluating COPD and may be superior to CT because it allows simultaneous visualization of airway and airspace structure and function at high spatial and temporal resolution, without x-ray radiation risk.
The team believes that imaging measurements can be used to determine the relative contributions of airway obstruction and emphysema in individual patients and furthermore provide a better way to stratify patients based upon underlying pathological changes. The stratification or differential phenotyping of COPD patients based upon different underlying pathologies has the potential to have a profound effect on patient management because the treatments required are likely very different.
Radiation-Induced Lung Injury
Radiation induced lung injury (RILI) is the major dose-limiting toxicity of lung cancer radiation. Due to the high oxygen content of the lung, it is extremely sensitive to radiation, with lung injury caused by radiation occurring in an estimated 5-35% of patients undergoing thoracic radiation, and the incidence of moderate to severe radiation injury between 10-20%. With increasing severity, survival rates decrease dramatically, and studies show that 3-year survival rates of 0% in subjects with severe injury. Given the high prevalence of RILI, the dismal survival rates in severe cases, and the fact that current methods provide only a slightly better than chance predictive value, new measurement tools are urgently needed. Recently, collaborators at London Regional Cancer Program have shown that currently used measurements have very low predictive value. The identification and quantification of new measurements (either alone or in conjunction with existing clinical and dosimetric parameters) with high sensitivity and specificity predictive of RILI development, severity, and progression are crucial, so that radiation planning can be adapted to maximize the risk/benefit ratio. Lung cancer and COPD are both diseases of tobacco smokers, thus many patients diagnosed with lung cancer will also have underlying COPD. Inflammation is also the hallmark of RILI leading to the hypothesis that in vivo imaging measurements of airway function (airway disease or inflammation) and airspace structure (emphysema) provide a way to predict the enhanced and prolonged inflammatory response to radiation. Therefore, it is possible that novel regional measurements of airway function and tissue destruction typical of COPD could be used to predict RILI. The team recently completed a pilot study of 3He MRI in patients with clinically confirmed RILI and measured target and non-target lung 3He MRI phenotypes. These results led to the current proposal to use hyperpolarized 3He MRI to measure the airway and airspace structure and function in patients prior to radiation to provide sensitive and specific markers for predicting the development, severity and progression of RILI. This predictive power will have a new and profound effect on patient care allowing for radiation treatment planning evaluation in identified high risk patients. Hyperpolarized 129Xe and 13C MRI techniques, specifically for detection of inflammatory/metabolic changes associated with RILI and acute respiratory distress syndrome (ARDS) are also currently under development.