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2012-2013

The Lung Association and its medical section, the Ontario Thoracic Society (OTS), work to promote respiratory health through medical research and continuing education. This Research Update provides a brief summary outlining the 16 projects funded by the Lung Association during the 2012-2013 year in Ontario. The OTS relies on experts from across Canada to review the proposals and is responsible for approving the grants and allocating the research budget. The Lung Association is proud of the class of academic excellence we support to improve the respiratory health of Canadians.

Research Funded (2012-2013)

Acute Lung Injury (ALI) →
Asthma →
Chronic obstructive pulmonary disease (COPD) →
Lung Disease →
Lung Infection →
Lung Transplantation/Surgery →
Smoking Cessation →
Research Grant Awards →

 


Acute Lung Injury (ALI)

Dr. Sean E. Gill, University of Western Ontario
TIMP Regulates Macrophage Function Following Acute Lung Injury

Acute lung injury that results from trauma, infection, or disease is often made worse by out-of-control inflammation. While the right amount of inflammation protects from infection and helps with proper healing, excess inflammation can have severe, detrimental consequences. Following lung injury, these severe consequences can include mortality, but they also include chronically decreased lung function in patients that survive, which leads to a decreased quality of life.

One type of inflammatory cell, the macrophage, is known to be able to start and stop inflammation following injury. A group of enzymes, called metalloproteinases, and their inhibitors, called tissue inhibitors of metalloproteinases (TIMPs), are thought to be important to macrophage function, but this has yet to be shown in lung injury. Our interest is in understanding how the macrophage stops inflammation following lung injury and specifically, what factors control how this cell functions.

We use a model of lung injury in mice that results in similar injury and inflammation as that found in patients with acute lung injury. Once the mice have lung injury, we isolate the inflammatory cells and analyze macrophage function. We also use mice that lack one of the metalloproteinase inhibitors (TIMP3) to examine how macrophages are controlled.

By the time most patients are diagnosed with acute lung injury, they already have inflammation present in their lungs. While a number of studies have identified what leads to the start of this inflammation, very few have shown what must happen to stop inflammation once it has started, which is the focus of our work.
Our studies will address important mechanisms of how inflammation is regulated and turned off following acute lung injury and may provide information regarding possible therapeutic targets. These therapeutic targets would potentially decrease mortality resulting from lung injury, but they would also decrease the damage that occurs as a result of excessive inflammation. Ultimately, this would improve lung function leading to enhanced quality of life of patients following recovery from injury.

Dr. Jim Lewis, Lawson Health Research Institute
The Role of Hypercholesterolemia in Susceptibility to Acute Lung Injury

Acute Lung Injury, or ALI, is the term used when the lungs become severely damaged due to conditions such as pneumonia, the aspiration of stomach contents or a systemic infection. When patients develop ALI, they often require a life support machine or mechanical ventilator (MV) to keep them alive; however the MV itself can cause damage to the lungs, often worsening the illness. This eventually results in inflammation, which can spill over from the lung into the bloodstream and affect other organs such as the liver or kidneys. When other organs become damaged there is a dramatic increase in the number of patients that die as a result of ALI. Despite more than 30 years of research in this area, there is currently no effective treatment for these patients.

Recently, our lab has found that genetically-modified animals that have high levels of cholesterol in their blood were more susceptible to ALI than normal animals. The results of this study are important for several reasons; i) this observation has never been described before, ii) elevated cholesterol levels are a common and growing problem in North America, and iii) if patients with high cholesterol levels can be identified early, more effective treatment options may be available to minimize the severity of this disease. This grant will therefore will help in developing better treatment options for this devastating condition, and also minimize health care costs associated with ALI.

Specific Aims #1-3 will address the following questions; 1) Do high levels of cholesterol predispose patients to be more susceptible to a specific type of injury to the lungs? ii) Does the ventilator itself cause more damage in the setting of high cholesterol levels? and iii) Does high cholesterol lead to an increased risk of damage to other organs in ALI? Specific Aim #4 will be to determine if animals with high cholesterol levels due to high dietary cholesterol intake have the same susceptibility as the genetically-modified animals.

We are using genetically modified mice that have high cholesterol levels as these types of studies are not feasible to perform in humans. Firstly, we will determine whether these animals show any difference based on the type of injury they sustain by comparing a model of stomach aspiration (by instilling acid into the lungs) with a model of pneumonia (by instilling a substance called LPS that mimics infection) and see if there is a difference in lung damage and inflammation. Secondly, we will compare ventilator technique to determine if these mice with high cholesterol levels are more susceptible to a specific mode of life support. Thirdly, we will measure inflammatory molecules released by the lung to determine if high cholesterol levels impact on this problem. Finally, we will feed normal mice a high fat and cholesterol diet for 4 weeks and do similar experiments and compare the results to the genetically modified animals.
Although elevated levels of cholesterol are an important contributor to the development of heart disease, it is unknown whether cholesterol can also lead to problems with the lungs. In some preliminary experiments, we tested genetically modified animals and found they were indeed susceptible. We want to expand our research in this area to determine how this susceptibility occurs, and whether it may be applicable to patients with high cholesterol. This is unique and important information which could potentially lead to new therapies for ALI and possibly other lung diseases prevalent in Canadians.

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Asthma

Dr. Roma Sehmi, McMaster University
Role of Thymic Stomal Lymphapoietin (TSLP) in Promoting Migration of Progenitor Cells in Asthma

When you cannot breathe, nothing else matters. Asthma is a chronic disease of the airways that affects more than 3 million people in Canada and its incidence is increasing. A recent study reported that one in every three individuals in Ontario would receive a physician diagnosis of asthma during their lifetime. Therefore despite the development of many anti-asthma drugs, many asthmatics continue to have worsening breathlessness as they grow older. Therefore the development of new drugs that can better manage these symptoms is of great importance. Investigating the biological processes that cause this disease may reveal novel targets for drugs to treat the continued breathlessness that worsens over time in people with asthma.

Increases in blood supply to the lungs (through increased formation of blood vessels in the lungs) can cause the narrowing of the airways by increasing the amount of fluid in the lungs and the supply of tissue damaging cells. The processes that contribute to increased blood vessel formation in asthmatic lungs remain unclear. In this study, we will investigate the processes that contribute to increased blood vessel formation in asthmatics lungs by investigating the effect of factors produced in asthmatic lungs that can encourage the movement of blood vessel precursor cells to the lungs and their maturation within the lungs to form blood vessels.

Using a laboratory method that can measure the movement of cells from one body compartment to another, we will investigate the effect that an important lung-derived factors have on the migration of blood vessel precursor cells. We will study the effect that this factor called thymic stromal lymphopoietin has directly on the migrational responsiveness of blood vessel precursors; as well as its indirect effects in promoting increased responses to other factors that stimulate the accumulation of the cells to the lungs. We will also investigate if precursor cells from people with asthma are more sensitive to the effects of this factor compared to cells from normal subjects with no disease. We will first study precursor cells from cord blood which we have found in our work to respond like blood extracted cells and is a sample that is readily available to our laboratory. Then we will collect blood from asthmatics and normal and compare the precursor responses from the two groups.

The role of precursor cells in the development of disease processes including asthma is a new and important field. Few groups are investigating this aspect of the disease and have mainly focused on mature cells. We have shown from our studies over the past two decades that precursor cells are involved in the early development of disease. Thus by investigating the effect of pathological factors that on the recruitment and function of precursor cells for blood vessels, we can propose unique drug targets for the optimal treatment of difficult to control symptoms of asthma.

Increased formation of blood vessels is a prominent feature of the asthmatic lung and studies have shown that this feature increases as the symptoms of this disease worsen. The findings of this study will provide a better understanding of biological processes that cause increased blood flow to the lungs in asthma and indicate whether controlling this aspect of the disease directly can help to treat symptoms of asthma that are difficult to control with the asthma drugs that are currently available.

Dr. Luke Janssen, McMaster University
Agonists of bitter taste receptors disrupt internal Ca2+ store and airway smooth muscle biochemistry

One of the main signs of asthma is constriction of the airways and reduction in the inability to breathe. This constriction is caused by a band of muscle which wraps around the airways (“airway smooth muscle”), and which is activated by chemicals from nerves or inflammatory cells. Those cause changes in the concentration of other chemicals inside the airway smooth muscle cells, including calcium, which then causes contraction. Several types of drugs that open the airways (“bronchodilators”) are available — such as β-agonists — but these do not fully control asthma. Many patients still suffer from serious asthma attacks which put them in the emergency room or sometimes even kill them. The major asthma drugs available have not changed for several decades: we desperately need a new therapy for asthma to complement the existing tools.

A recent study found certain bitter compounds produce bronchodilation superior to that of the β-agonists. This effect appears not to involve the same signalling pathway used by the β-agonists, but is instead associated with a release of calcium stored inside the airway smooth muscle cell. The rise in calcium concentration which results then opens upcertain ion channels (potassium channels) and causes an electrical change (hyperpolarization) which seems to cause the relaxation. However, several questions remain unanswered, including how/why a bronchodilator releases a unique pool of internally stored calcium (the opposite effect would normally be expected, given that chemicals which cause contraction are widely recognized to act by releasing internal calcium) and what role is played by the electrical changes within that mechanism.

We will cut thin slices of human or murine lungs and load them with a dye which will let us simultaneously monitor changes in calcium concentration and airway diameter. Strips of airway smooth muscle will be attached to a force sensor in order to record contractions/relaxations. Alternatively, enzymes will be used to break the tissue strips down into single cells which can be studied under the microscope and special electrodes used to measure electrical changes. All of these distinct but complementary techniques will allow us to see how changes in calcium and electrical signals produce a contraction or relaxation. We will use these techniques to examine the actions of the bitter compounds against contractions evoked by a major neurotransmitter (acetylcholine) or a major inflammatory mediator (leukotriene), and to make comparisons with the corresponding actions of β-agonists.

The recent report of the bronchodilatory actions of bitter compounds has excited a great deal of interest in the airway smooth muscle / asthma community. Their findings were quite provocative: that a bronchodilator acts by releasing internally stored calcium (since the opposite would be expected to happen) and hyperpolarizing the membrane through opening of K+ channels (since airway smooth muscle is not normally so sensitive to voltagedependent mechanisms, at least not nearly to the extent that arteries and other muscles are). However, we have offered alternative re-interpretations of their data, and have added to that our own preliminary data which support our novel hypothesis: that disrupting the internal calcium store leads to a complete switch in the way the cell links calcium changes to contraction. In this application, we provide 4 different sets of experiments which will test this hypothesis.

There are 5 major classes of asthma drugs which act specifically on the airway smooth muscle (β-agonists; anticholinergics; anti-histamines; anti-leukotrienes; phosphodiesterase inhibitors). However, these are not sufficient to fully control asthma — many still suffer with or even die from this disease — and no new major classes have been identified in the past 20 or 30 years. The recent study of the powerful bronchodilatory actions of bitter compounds offers hope in this regard: a better understanding of how they work might lead to a whole new approach to the treatment of asthma.

Dr. Mangalakumari Jeyanathan, McMaster University
Effects of pre-existing Bacillus Calmette-Guerin induced Immunity in the development of experimental allergic asthma

Asthma sufferers are increasing worldwide. Conventionally it is believed that external influences on the immune system via natural infections or immunization with live attenuated bacterial vaccine in early life can protect against asthma. Accordingly it is proposed that high prevalence of asthma in industrialized countries is owing to decreasing incidence of infections in early life. Conversely, despite of high prevalence of infections and wide coverage of a live attenuated bacterial immunization programme in early life, in developing countries asthma is becoming a major health issue. This positive relationship between early life infections and asthma contradicts the conventional wisdom. Unfortunately, currently available information as to whether or not early life infections or immunization with live attenuated bacterial vaccines protect against asthma is controversial. This is partly because of unavailability of in depth experimental studies on physiologically relevant animal models.

The objective of the current project is first to establish a physiologically relevant animal model to discover whether or not prior immunization with live attenuated bacterial vaccine protects against development of asthma. Secondly to characterize the immune responses in these models to investigate the mechanism(s) by which immunization with live attenuated bacterial vaccine regulates asthma outcome.

The current study set out to address an under-investigated but yet an important question of whether or not early life infections have an influence in the development of asthma. Clearly, in depth understanding of the influences of early life infections on the immune system and subsequent impact in the development of asthma is critical for reforming our scientific views. In addition, we hope that detailed study of immunological responses in this study will allow us to identify therapeutic targets to treat asthma.

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Chronic Obstructive Pulmonary Disease (COPD)

Dr. Kjetil Ask, McMaster University
The role of the chaperone FKBP13 and ER Stress in cigarette smoke induced pulmonary disease

Chronic Obstructive Pulmonary Disease (COPD) has become one of the leading causes of mortality and morbidity over the last decades in North America. Some of the known causes of COPD are cigarette smoke exposure, dust exposure, bacterial and viral infections. The exposure to these factors alone or in combination has a profound effect on the expression of genes and proteins in the lungs of COPD patients. As a consequence proteins may not be built in the correct manner by the cell and may be dysfunctional. It has been shown that the accumulation of not properly folded proteins can lead to development of disease in the lung or elsewhere in the body, for example in the case of cystic fibrosis, diabetes and Parkinson disease. It is important to study if cigarette smoke triggers “misfolding” of proteins and thereby contributes to the development of COPD. A better understanding of these underlying fundamental processes may help to develop better treatment for COPD.

Mice that are deficient in a molecule thought to be involved in the protein folding and trafficking (chaperone) will be exposed to cigarette smoke. We will assess markers that indicate whether misfolded proteins are accumulating in lung cells derived from these animals. In addition, we will assess lung physiology, as we expect that the chaperone deficient mice will have a significantly worse outcome.

We will expose mice, which are manipulated to be deficient of a molecular chaperone to cigarette smoke. We will then assess specific markers that indicate if protein folding was completed successfully and if misfolded proteins are accumulating in the cells. We will assess changes in lung physiology as we expect that the chaperone deficient mice will have a significantly worse outcome in response to cigarette smoke exposure.

It has been shown that accumulation of misfolded proteins contributes to worsening of a number of apparently unrelated diseases (cancer, diabetes, cystic fibrosis, atherosclerosis). Evidence suggests that these mechanisms may also contribute to the pathogenesis of COPD, although there is only limited data available. This proposal is novel as it addresses the role of the unfolded protein response to inflammation and tissue pathology in a murine model of cigarette smoke exposure. This, we feel, may be a great opportunity to learn more about the importance of protein misfolding and to identify novel therapeutic targets.
Many chronic lung diseases are of unknown origin and it is critical to elucidate the underlying molecular mechanisms and pathways leading to disease. Once pathways and molecules are clearly documented to contribute to disease expression and/or progression, therapeutic strategies can be developed. This proposal aims to identify and characterize the role of disturbed protein folding as a mechanism contributing to cigarette smoke-induced disease. The Lung Association places a high priority on ensuring that the funded research is relevant to its mission.

Dr. Roger Goldstein, West Park Healthcare Centre
A Randomized Controlled Trial of a post-rehabilitation Community-based exercise program for individuals with COPD
*OLA/Pfizer Award

It is well established that individuals living with chronic obstructive pulmonary disease (COPD) demonstrate significant improvements following a formal rehabilitation program. The problem lies in the fact that these functional improvements diminish over a 12 month period. This decline in function is associated with decreased participation, a decline in health status, and an increased need to access the healthcare system.
The objective of this project is to evaluate the effectiveness of a post-rehabilitation community-based exercise program for individuals with COPD and compare the outcomes with those achieved through standard care.

Individuals with COPD who have completed a previous rehabilitation program will be enrolled in the study. Study participants will be assigned randomly to either a year-long community exercise program or usual care. Those assigned to the community program will exercise twice weekly at a local community centre supervised by trained fitness instructors. A case manager will facilitate the transition from the hospital rehabilitation program to the community centre. The case manager will also be available to participants and instructors for consult as needed. Continuing to build on an established partnership with the City of Toronto, the case manager will ensure fitness instructors receive specialized training in order to properly supervise and support the individuals with COPD. Participants assigned to usual care group will receive standard care by their family physician and respiratory specialist. Functional status will be evaluated before the program begins and again at 6-months and 1-year. The outcome of each group will be compared to determine the effectiveness of the community exercise program.
This proposal is novel as it is a model of integrated and seamless care from institution into the community for individuals with COPD. Specifically, this proposal is innovative for the following reasons: 1) patients are integrated into a community setting and away from health care institutions; 2) the exercise program is supervised by fitness instructors and not health care professionals rendering it cost effective; and 3) a case manager is available to participants and fitness instructors for consult 24 hours a day, if needed.

The proposed research fits seamlessly with the mission of The Lung Association as it has the potential to empower individuals living with COPD to self-manage their condition in a supported environment. It extends the observations made in our pilot study funded by the Lung Association, which noted the success of a community-based exercise program for maintaining wellness and exercise capacity, to the next step, namely a randomized controlled trial. Should participation in a community-based maintenance exercise program result in the improved maintenance of functional exercise capacity compared to standard care, this approach will represent an innovative and inexpensive strategy to optimize the maintenance of gains made during pulmonary rehabilitation.

Dr. Renee Labiris, McMaster University
Imaging Lung Function in COPD using SPECT/CT

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. This disease is a collection of pathologies including chronic bronchitis, chronic bronchiolitis and emphysema. These pathologies cause the partially irreversible airflow limitation that is the hallmark of COPD. Patients with COPD may have a specific pathology or a combination of different ones. COPD is potentially treatable and its progression slowed when detected early. Diagnosis and disease monitoring is primarily based on pulmonary function tests (PFTs). However, PFTs are insensitive to early and small pathological changes, not capable of explaining the biological cause of airflow limitation, and do not identify the affected region of lung.

Because COPD is a collection of diseases, knowing the type, extent and location of pathologies and their functional consequences may lead to earlier and more precise disease definition, prognosis and treatment. Ventilation and perfusion (V/Q) imaging, performed with single photon emission computed tomography (SPECT), measures levels of airflow (ventilation) and blood-flow (perfusion) in the lung. The overall objective of the proposed research is to investigate whether V/Q SPECT is sensitive to COPD-driven changes in lung function. To accomplish this, we will first determine if the type of V/Q mismatching is dependent on the type of pathology present, such as emphysema and airway inflammation using established animal models of COPD compared to the traditional method of measuring lung function in rodents.

We will use three mouse models of COPD having either a specific pathology or combination of different ones in order to map V/Q mismatching to areas of pathological abnormalities using established functional and anatomical imaging techniques. We will compare these findings to well-established lung mechanics and histological measurements.

Applying a common clinical method of performing V/Q imaging to mouse models of a disease, allows us to perform preclinical studies that would be clinically impossible to study the functional consequences of known COPD phenotypes. By combining a novel automated regional 3D quantitative image analysis with V/Q SPECT we can objectively investigate lung physiology at a regional level. In the future, this will allow physicians and researchers to understand how certain pathologies affect lung function, identify malfunctioning tissue areas for lung volume reduction surgery, screen novel therapies, and develop drug targeting strategies.

We believe that knowing the presence, degree and location of abnormal lung function using V/Q SPECT, a test readily available in all nuclear medicine departments, will lead to earlier and more precise diagnosis, prognosis and treatment of COPD and thus reduce the burden of this disease on our healthcare system. This work will provide an experimental platform on which to study disease progression and pre-screen future therapeutics. We believe that these goals are fully relevant to the mission of the Lung Association.

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Lung Disease

Dr. Neil Sweezey, Hospital for Sick Children
Regulation of Perinatal lung development by glucorticoid responsive signalling in mesenchymal cells in vivo

Chronic lung injury (Bronchopulmonary Dysplasia, BPD) affects over one third of babies born prematurely and weighing less than 1 kg. The damage to their underdeveloped lungs can have bad effects that last a lifetime and cause major costs to the healthcare system. Treatment with steroid hormones (glucocorticoids) can stimulate biological messengers (glucocorticoid signalling) that improve lung function in BPD, but bad effects of steroids on newborn brain and lung mean that they are generally no longer used for treatment of this condition. Since there is still no safe and effective treatment or prevention for BPD, we are trying to better understand how glucocorticoids stimulate lung development. We believe this may permit us to find messengers that will stimulate lung development without causing the bad effects of the glucocorticoids themselves.

It has been assumed that the glucocorticoid signalling needed for lung development is present in the type of lung cells called mesenchyme. We are using mice genetically engineered to lack glucocorticoid signalling in mesenchyme to help us identify which proteins made by this cell type are involved in lung development. We will compare these mice with normal mice with respect to their lung development during the critical newborn period.

Our mice were genetically engineered for the purpose of doing this study. We are not aware of anyone else who has such mice that survive after birth except for scientists who are working with us. There is no safe and effective treatment or prevention for chronic lung disease of the prematurely born (BPD). Encouraged by our preliminary results, obtained during our first five months of Lung Association funding, we expect that the results of this project will help us find proteins (or modifiers of protein production or function) that may be able to improve the health of the lungs of newborn babies with BPD, without causing the bad effects of steroids. Since premature birth and newborn lung injury increase the long term risk for respiratory health, the work that we propose to do may be important not only for BPD, but also for asthma, emphysema and chronic obstructive pulmonary disease (COPD). Asthma affects many adults as well as children. Emphysema and COPD are quite common conditions of adults.

Dr. Louise Rose, University of Toronto
Healthcare Costs and Utilization of Long-Term Users of Mechanical Ventilation in the Home

In Canada the number of people that require long-term assistance from breathing machines (ventilators) as a result of serious illness or progression of chronic disease continues to increase. Many of these ventilated assisted individuals (VAIs) choose to live at home to promote quality of life, despite the potential physical, psychological and financial burden for them and their families. In Canada, there is little information describing the healthcare use and financial costs of caring for VAIs living at home. There is also little known about the factors that may increase or decrease costs such as type of ventilation (by a tube in the throat or mask/mouthpiece) or health-related quality of life (HRQoL).

The Objectives of the study are:1) to assess the patterns of healthcare use and cost of VAIs living at home in Ontario; 2) to examine factors that may increase or decrease costs; 3) to describe caregiver burden experienced by family caregivers; 4) to describe HRQoL of VAIs and their family caregivers; and 5) to examine factors that may increase or decrease HRQoL of VAIs. We will interview VAIs and family caregivers every 2 weeks for 6 months. Details of both public and private healthcare expenditures will be collected, including healthcare appointments, travel, out-of-pocket expenses and time devoted to caregiving. HRQoL, caregiver burden, and ability to perform daily activities (VAI only) will be collected at the start of the study and every 3 months using validated measures. We will recruit 195 VAIs and their caregivers. VAIs will be eligible if they are: using ventilation for ≥ 6 hours per day; ≥ 16 years old; able to read and write English; live at home; do not have obstructive sleep apnea as the primary reason for mechanical ventilation; and agree to participate. Caregivers will be eligible if they are able to read and write in English; ≥ 18 years old; and agree to participate. We will recruit participants primarily through the Ventilator Equipment Pool, an organization that loans ventilator equipment and supplies to VAIs living in the community in Ontario.

This study is unique as it applies previously developed and validated methods to prospectively (looking forward in time thus minimizing reliance on participant memory) assess healthcare use and financial costs in a new population, VAIs living at home. Little data describes healthcare use and financial costs either in Canada or internationally; the small number of previous studies have been conducted retrospectively (asking VAIs to remember healthcare visits and costs) and have not assessed both public and private costs including those of family caregivers e.g. missed time from work, leisure time lost or household work. As well this study will be the first to describe factors that explain why some VAIs and their families have higher healthcare costs than others.

Our study population require the highest level of respiratory support – mechanical ventilation and extends to many respiratory diseases, disorders or syndromes leading to long-term ventilation. Our project aims to assist VAIs and their families manage lung disease and optimize lung health by providing a description of current healthcare utilization and financial costs. This information will inform policy makers to distribute funds and support that would optimally support VAIs and their families living at home promoting lung health and quality of life. This may include the development of effective, consistent and cost-efficient programs aimed at prevention of complications, health management and health promotion. The results of this project will be shared with clinicians, VAIs and families to inform collaboration and partnerships across health sectors, professions, and jurisdictions. This will ultimately improve health outcomes, patient safety, and HrQoL for our target population.

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Lung Infection

Dr. Dawn Bowdish, McMaster University
Age-associated pneumonia results from impaired immune control of nasopharyngeal carriage
*OLA/Pfizer Award

Pneumonia is the sixth most common cause of death in Canada. The incidence of pneumonia rises steeply in individuals over the age of 65 years and approximately 90% of deaths due to pneumonia occur in the elderly (>65 yrs). Current prevention strategies are inadequate as the vaccination does not prevent pneumonia in most elderly individuals. Our recent data demonstrate that one of the reasons the elderly are so susceptible to pneumonia is that their immune systems cannot control the bacteria that normally live in our sinuses. The immune systems of healthy adults can keep the bacteria in the sinuses and eventually clear them, but for reasons we don’t understand, the immune systems of the elderly cannot and as a result the bacteria break through the immune barriers of the sinuses and spread to the lungs, which results in pneumonia.

Although most people think that the elderly get sick because their immune systems “just don’t work”, in fact our data demonstrate that they recruit more white blood cells to the sinuses when they encounter the bacteria that cause pneumonia than healthy adults. Even though they have more white blood cells in the sinuses they don’t seem to be as good at recognizing and killing bacteria. Our goal is to figure out why they have overactive recruitment of white blood cells and why they aren’t as good at killing bacteria as white blood cells from healthy adults.

By using white blood cells derived from young and elderly individuals we can test whether recognition and killing of bacteria is impaired in the elderly. We also have a mouse model in which we use Adult mice (10-14 weeks, equivalent of a 20-25 year old person) and Old mice (18-22 months, equivalent to a 75-85 year old person). By putting bacteria in the sinuses (“colonization”) of these mice we can measure white blood cell recruitment and gene expression.
We have developed what we believe to be the world’s only Aged mouse model of colonization by pneumonia causing bacteria. This allows us to study how the immune system responds to the presence of bacteria in the sinuses in real-time. In addition we have a bank of white blood cells from adults and elderly patients that allow us to confirm the importance of our mouse studies in people.

Hospitalizations and deaths due to pneumonia are unacceptably high in the elderly. This is likely because vaccination of the elderly only does not protect against pneumonia. New methods for preventing infection are urgently required. Our recent data demonstrates that containment and clearance of pneumococcal carriage is impaired in age and results in increased susceptibility to pneumonia; however the mechanisms by which immune control of the sinuses fails remain to be discovered. Prevention of colonization of the sinuses will therefore be essential for control of pneumonia in this population. In order to develop novel therapeutic interventions for the elderly it will be necessary to discover the mechanisms by which bacterial recognition, killing are impaired in the sinuses. This research would use a new test to see if movement of TB between people is different in the colder communities in the Canadian north. It would also help health-care professionals come up with new ways of preventing people from being infected with TB in Aboriginal communities across Canada.

Dr. Theodore Marras, Toronto Western Hospital/UHN
The risk of mycobacterial infections associated with TNF-α antagonists in Ontario

Tuberculosis (TB) is a world-wide public health problem. TB infection can affect any organ, but most commonly infects the lungs and is usually fatal if untreated. TB can make anyone sick, but people with weak immune systems are more likely to get TB. Nontuberculous mycobacteria (NTM) are germs found in soil and water and are closely related to the germ that causes TB. NTM germs are found all around us and usually do not cause disease in humans. Sometimes NTM can infect humans and cause severe disease, usually in the lungs, that is extremely difficult to treat. NTM lung disease has become much more common over time. We do not know why NTM infects some people, but a weak immune system or chronic lung diseases put people at risk.

Tumor necrosis factor (TNF) blockers are very important and commonly used medications for rheumatoid arthritis and other chronic inflammatory diseases. They block the action of TNF, a molecule that causes inflammation. Unfortunately, TNF is also important in the body’s immune system, because it helps fight TB and NTM infections. TNF blockers increase the risk of TB, but the extent of the risk is not clear. It is unclear whether TNF blockers also increase the risk of getting NTM lung infections. We will determine if TNF blockers increase the risk of NTM infections and TB in people in Ontario, and measure the extent of this risk. We will combine data from Ontario’s Public Health Lab (records of Ontarians who had TB or NTM germs identified), and at the Institute for Clinical Evaluative Sciences (records of Ontarians treated with TNF blockers) to learn how many people in Ontario treated with TNF blockers developed TB or NTM infections. We will compare the rate of infection in people using TNF blockers with the rate of infection in people not taking TNF blockers to see if TNF blockers really are a risk factor, and if so, how big.

There have not yet been any published studies of the risk of NTM infection with TNF blockers. Also, our work will be the first population-based study of TNF blockers as a risk factor for TB or NTM, and the first Canadian study of this problem. No previous study included all patients in a population or community, and none have been done in Canada.

It is known that TNF blockers increase the risk of TB. It is not known how big that risk is. Our study will measure the risk. This knowledge will help doctors and patients make better decisions about screening and treatment for TB when a TNF blocker is being considered, and prevent cases of TB in Canadians.
It is not known if TNF blockers increase the risk of NTM lung infection. Doctors who prescribe TNF blockers do not check their patients for NTM infection. With the information from our study, doctors will know if it is important to check patients for NTM infection before they start TNF blockers (and possibly while they continue treatment) to reduce the number of severe cases of NTM lung infections in Canadians.

Dr. Samira Mubareka, Sunnybrook Research Institute
Characterization of influenza virus laden infectious Bioaerosols

Influenza virus is responsible for annual deaths due to seasonal epidemics and is the cause of major pandemics, which have claimed the lives of millions of people over the course of the last century. Surprisingly, little is known about how the virus is transmitted person to person. There is little doubt that spread is through the air, but we don’t know the characteristics of the aerosols produced by infected individuals.

We aim to characterize the aerosols produced by 2 groups of subjects infected with influenza virus. The first is a group of experimental animals (in this case, guinea pigs) experiencing laboratory-controlled influenza virus infection. The second group is one of naturally-infected humans. We intend to look at the spread of the aerosols, the particle content (number and size), and how the aerosols change under different environmental conditions in the experimental animals.
We will use biocontainment facilities at Sunnybrook Research Institute to perform experiments characterizing aerosols generated by influenza virus-infected guinea pigs. We will use a special air sampler capable of testing for live influenza viruses. Naturally-infected humans will be assessed in a fluid dynamics laboratory at the University of Western Ontario, using the same sampler as well as a sophisticated laser-based system to gain an understanding of the speed at which particles produced by infected humans are generated and dispersed.

For decades, work in infectious aerobiology has been done by the military and many of the findings are not in the public realm. Since SARS, the scientific and medical communities, as well as the general public, have gained an appreciation of the public health importance of respiratory virus transmission. Although coughs have been characterized, very little work has been done to examine coughs from infected individuals; we will do so in a unique and detailed fashion. In addition, we are using a new generation of air sampler which is the first in its class capable of recovering live virus.

By gaining an understanding of the aerosol transmission of influenza virus, we hope to uncover possible means by which to abrogate influenza virus transmission and reduce morbidity and mortality from severe and complicated influenza. Due to the experimental and methodological challenges of transmission studies, this area has not profited from extensive study. The importance of developing expertise and knowledge in this field was underscored during SARS, where healthcare workers, in particular, suffered from infection. With recent technological developments in the area of aerobiology, we are now well-positioned to develop this knowledge base.

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Lung Transplantation/Surgery

Dr. An-Wen Chan, Women’s College Hospital/University of Toronto
Burden of Cancer after lung transplantation
**Breathe New Life Award

As a life-saving procedure for patients with severe lung disease, over 1,300 lung transplants were performed in Canada from 2001 to 2009, with almost half being performed in Ontario. Survival after lung transplantation has improved over the past decades. With increased survival, the long-term complications of anti-rejection drugs – which are needed to prevent rejection of the transplanted lung – have become more prominent. In particular, long-term use of these drugs increases the risk of cancer.

Cancer is now a leading cause of illness and death after lung transplant, accounting for 11% of deaths after the first year. Lung transplant patients are 65 times more likely to develop skin cancer and 7 times more likely to develop other cancers compared to the general population. One in 4 lung transplant patients develops cancer within 10 years after transplant. Data from a large population are needed to inform the prevention, detection, and prognosis of cancer in this high-risk group of lung transplant patients in order to improve their long-term health and quality of life.

To determine 1. How often cancer occurs among adults receiving lung transplantation in Ontario from 2001-2009; 2. Whether the development of skin cancer and other non-skin cancers leads to shorter survival after lung transplant (and if so, by how much); and 3. How often these patients have skin exams and burdensome treatment for skin cancer, the most common cancer after lung transplant.

We plan to study all adults (about 500) who receive a lung transplant from 2001-2009 in Ontario. We will use provincial health and administrative databases to identify data on each of these lung transplant patients. Data to be collected include cancer diagnoses, death, and their risk factors (anti-rejection drug usage, age, sex, race, diabetes, smoking status, any cancers prior to transplantation). We will calculate how often and when cancer occurs after lung transplantation; how much these cancers shorten survival compared to patients without cancer; and how often these patients undergo screening and extensive surgeries, chemotherapy, or radiation for skin cancer.

We propose the first study of cancer burden and outcomes in a large, representative population of lung transplant recipients. Previous studies have examined patients at a single university, or relied on voluntary reporting of data that may not have been complete. Secondly, we have access to an unprecedented amount of detailed patient-level data for a province-wide group of patients. Specifically, our ability to obtain data on key cancer risk factors such as race and anti-rejection drug levels is unique to this study. Finally, we plan to create a unique population-based dataset of anti-rejection drug usage, which can be leveraged for future studies linking these drugs to other long-term complications after lung transplant (e.g., heart disease, infections).

Lung transplants are a potentially life saving treatment for people with severe lung disease. Given the scarcity of lung donors and the risks involved with transplantation, it is important that everything possible is done to maintain long-term health and quality of life for these patients. Results from this study of Ontario patients can improve the health of lung transplant patients in several ways. Firstly, if transplants lead to cancer that could result in a premature death, this is a problem that needs to be addressed with early screening, prevention, and modifying anti-rejection drug dosages. Cancer prevention would contribute to the improved overall success of the lung transplantation. The study will also provide useful information on the burden of skin cancer that can affect their quality of life, and will enable clinicians to counsel patients about the impact of cancer on their prognosis. Ultimately, our study aims to enhance the survival and quality of life of lung transplant patients by informing cancer prognosis, improving early cancer detection, and guiding appropriate treatment in this high-risk population.

Dr. Chung-Wai Chow, University Health Network
Syk Inhibitors: Role in Management of Chronic Allograft Dysfunction following Lung Transplantation

Lung transplantation is the only viable treatment option for patients with endstage lung disease. Chronic rejection following transplantation is the most common obstacle to long-term survival. It occurs in 50% of patients by year 5 and 75% by year 10 following transplantation. This leads to loss of lung function, decreased quality of life, and increased mortality. Indeed, chronic rejection is the most common cause of death at 5 or more years after transplantation. The underlying mechanisms that lead to chronic rejection are not fully known, and no effective treatment is currently available for management.
Studies in my laboratory using a genetically modified mouse have shown that loss of Syk, a key regulator of our immune response, prevents development of airway occlusion and the typical changes seen in the lungs of patients with chronic rejection – called obliterative bronchiolitis. Syk inhibitors are now available. Their role in preventing chronic rejection following lung transplantation is not known.

The primary goal of the project is to evaluate the effectiveness of Syk inhibitors in preventing the development of obliterative bronchiolitis (OB), the typical airway lesion found in chronic rejection following lung transplantation.

We will use a mouse model of OB and the Syk inhibitor, R788, that is currently in phase 2 clinical trials. The mouse model of OB is a robust and well-validated model that has been used extensively to study chronic rejection post lung transplantation. In this model, the trachea of one strain of mouse is transplanted into the lungs of a recipient mouse of a different strain (simulating the human donor/recipient scenario). Under these conditions, the typical changes of OB are seen at day 28 post transplant. To assess the effectiveness of R788 in preventing OB, we will treat one set of mice with R788, administered by mouth, and compare them to mice treated with placebo control. At 28 days post transplant (a time-point when OB is well-established in this model), mice will be sacrificed and the graft examined for development of OB.

Several novel Syk inhibitors have shown promise as an effective and safe therapy in patients with inflammatory disorders where chronic inflammation and tissue remodeling is prominent. A recent phase 2 study of 457 patients with rheumatoid arthritis have shown clinical efficacy and excellent safety profiles of the orally-administerd Syk inhibitor, R788. More importantly, opportunistic infections were not observed. Clinical trials and animal studies have also shown Syk inhibitors to be readily bioavailable when given directly into the airways.

Therefore, if our studies in mice show Syk have an important role in the development of chronic rejection post transplant, we intend to proceed to pre-clinical studies in patients. Moreover, the option of effective inhalational delivery of Syk inhibitors offers a significant advantage as a potential therapeutic agent in the lung transplant population by delivering high drug concentrations locally while minimizing systemic exposure.

For patients with endstage lung disease, lung transplantation is the only therapy that offers improved survival and quality of life. Unfortunately, availability of transplantation is limited by availability of donor organs. Thus, it behooves us identify treatment strategies to preserve lung function and improve outcomes in those who have been transplanted.

Dr. Yaron Shargall, McMaster University/St. Joseph’s Healthcare Hamilton
The Effects of Perioperative Non-Steroidal Anti-inflammatory Drug Naproxen on Pleural Effusions Formation After Lung Resection

When a cancerous tumour or other mass is found in a person’s lung, a thoracic surgeon will perform a lung resection to remove the tissue mass. As a side effect of this type of surgery, pleural effusion, or a collection of fluid in the pleural cavity, often occurs. In normal life, the amount of fluid in the area surrounding the lung (the pleural cavity) is balanced as it is created and absorbed by the body in equal amounts. After lung surgery, the amount of fluid created is significantly more because of inflammation and the cutting of lymph nodes. Chest tubes are inserted into the lung to drain this fluid. At this point in time, there is little thoracic surgery research into the effect of inflammation on the production of pleural effusions but cardiac surgery research has suggested that Non-Steroidal-Anti-Inflammatory Drugs (NSAID) help limit inflammation after surgery. In this research, it has been found that NSAIDs helped reduce pericardial effusion (fluid in the area around the heart) and also pleural effusion. It is desirable to find methods of reducing the amount of pleural effusion because the threshold where chest tubes are removed depend on the draining fluid volumes being below a specified amount.

This study will compare the amounts of pleural effusion after lung resection surgery at St. Joseph’s Healthcare Hamilton between a group receiving Naproxen, a well-tolerated NSAID and a group receiving a placebo. This study would like to identify that with NSAID treatment, there will be a decreased production of pleural effusion due to the anti-inflammatory properties of Naproxen. Patients undergoing lung resection will be randomly sorted into one of two groups to be treated for 30 days. The first group will take twice daily 500mg of Naproxen and 40mg of Pantoprazole, a Proton Pump Inhibitor, to counteract the stomach acid complaints Naproxen is known for. The second group will take an identical, non-active placebo and 40mg Pantoprazole. The amount of fluid collected from the chest tubes will be recorded and compared. Should this project show that NSAID use after lung resection surgery helps limit pleural effusion while maintaining patient safety, this study has the potential for practice change in thoracic surgery leading to a possibility of shorter duration of chest tubes and shorter hospital length of stay.

One mandate of The Lung Association is to help people manage lung disease. This project’s successful outcomes will help persons with lung tumours recover faster and more successfully from lung surgery by reducing the amount of pleural effusion which in turn limits some of the complications relating to fluid in the lung such as infections or difficulty breathing. Patients will be able to return home sooner and return to everyday life which in turn influences their overall quality of life.

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Smoking Cessation

Dr. Bernard LeFoll, Centre for Addiction and Mental Health
Exploring the effects of prazosin on nicotine-induced dopamine release in humans: A [11C]-PHENO PET study

In 2002, smoking among Canadians accounted for an estimated $17 billion in health care costs and over 37,000 deaths. Indeed, cigarette smoking is the leading preventable cause of mortality worldwide and contributes to substantial economic and health burdens in Canada. The need to continue to advance novel smoking cessation therapies is clearly evident. While the use of PET imaging technology in treatment seeking nicotine independent individuals can help elucidate the mechanism by which potential therapies may work, very few studies have assessed the effect of potential therapies on the living brain.

Recent evidence suggests that prazosin, a safe and effective medication for hypertension, reduces nicotine self-administration and relapse in animal models of nicotine dependence. Prazosin is known to block noradrenergic receptors in the brain. Our group is currently the first to evaluate prazosin as a novel medication for smoking cessation in humans. The aim of this proposed project is to assess whether prazosin’s effects on smoking are a result of modulating nicotine induced dopamine release in the brain, as has been previously shown by us in animals.

We will recruit participants from our current prazosin study which will involve adult smokers participating in two brief medication phases (15 mg/day prazosin versus placebo). During each medication phase, participants in the proposed project will undergo two PET scans – one after not smoking, and one after smoking. Additionally, participants will complete measures of nicotine craving and withdrawal during each scan.

This project will produce the first data in humans linking a potential smoking cessation therapy, prazosin, to the dopamine system in the living human brain. In addition, unlike most previous studies that have used the imaging molecule [11C]-raclopride, we will use a newly developed molecule called [11C]-(+)-PHNO. The sensitivity of this new molecule in detecting dopamine levels in the brain may be more sensitive than [11C]-raclopride, and thus allow for more accurate measurements.

Cigarette smoking is the chief cause of lung disease and the leading cause of preventable mortality in Canada and worldwide. The proposed study will help illuminate the mechanism by which prazosin may work, and thereby support a role for not only prazosin in smoking cessation, but also similar medications which influence the noradrenergic system. If we are able to justify a larger study with our results and are subsequently able to show that prazosin effectively attenuates smoking induced dopamine release, the proposed research could lead to greater smoking cessation and improved lung health outcomes for many people in Canada and beyond.

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Research Grant Awards

All grants are awarded based on ranking by national peer review process conducted by the Canadian Thoracic Society. Budget totaling $1.3 million, funding was approved for 16 of the 37 applications to be distributed in descending order of priority, based on their calculated national percentile ranking.

Approved and Recommended for Funding (alphabetically):
Amount Awarded
Dr. Kjetil Ask, St. Joseph’s Healthcare Hamilton/McMaster University
The role of chaperone FKBP13and ER stress in cigarette smoke induced pulmonary disease
$50,000
**OLA/Pfizer Award Recipient
Dr. Dawn Bowdish, McMaster University Immunology Research Centre
Age-associated pneumonia results from impaired immune control of nasopharyngeal carriage
$50,000
*Breathe New Life Award
Dr. An-Wen Chan, Women’s College Hospital, University of Toronto
Burden of cancer after lung transplantation
$49,964
Dr. Chung Dr. Wai Chow,University of Toronto
Syk Inhibitors: Role in Managementof Chronic Allograft Dysfunction following Lung Transplantation
$50,000
Dr. Sean E. Gill, The University of Western Ontario
TIMP3 Regulates Marcophage Function Following Acute Lung Injury
$50,000
**OLA/Pfizer Award Recipient
Dr. Roger Goldstein, West Park Healthcare Centre
A randominzed controlled trial of a post-rehabilitation community based exercise program for individuals with COPD
$50,000
Dr. Luke Janssen, McMaster University
Agonists of bitter taste receptors disrupt internal Ca2+ store and airway smooth muscle biochemistry
$50,000
Dr. Mangalakumari Jeyanathan, McMaster University
Effect of pre-existing Bacillius Calmette-Guerin induced-immunity in the development of experimental allergic asthma
$24,985.50
Dr. Renee Labiris, McMaster University
Imaging Lung Function in COPD using SPECT/CT
$49.903
Dr. Bernard LeFoll, Centre for Addiction and Mental Health
Exploring the effects of prazosin on nicotine-induced dopamine release in humans: A [11C]-PHENO PET study
$50,000
Dr. Jim Lewis, Lawson Health Research Institute
The Role of Hypercholesterolemia in Susceptibility to Acute Lung Injury
$49,400
Dr. Theodore Marras, University of Toronto
The risk of mycobacterial infections associated with TNF-α antagonists in Ontario
$49,307
Dr. Samira Mubareka, Sunnybrook Research Institute
Characterization of influenza virus laden infectious bioaerosols
$24,985
Dr. Louise Rose, University of Toronto
Healthcare Costs and Utilization of Long-Term Users of Mechanical Ventilation in the Home
$49,265
Dr. Roma Sehmi, McMaster University
Role of Thymic Stomal Lymphopoietin(TSLP) in Promoting Migration of Progenitor Cells
in Asthma
$50,000
Dr. Yaron Shargall, McMaster University
The effect of perioperative Non-Steroidal Anti-Inflammatory Drug Naproxen on pleural effusions formation after lung resection
$49,680
Dr. Neil Sweezey, Research Institute, Hospital for Sick Children
Regulation of Perinatal lung development by glucocorticoid responsove signalling in mesenchymal cells in vivo
$49,972

 

Notes:

* OLA/OTS Breathe New Life Award: The funds for the “Breathe New Life Award” are partly raised by the OTS members through the Top It Up! For Respiratory Research fund. This fund enhances the nationally reviewed and acclaimed Grant-in-Aid research competition and funds grants above and beyond the normal value of the GIA budget provided by the Ontario Lung Association (OLA).

**OLA Pfizer matching awards in Infectious Disease and COPD, respectively.

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