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Research Funded (2011-2012)

Air Quality→
Acute Lung Injury (ALI) →
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Air Quality

Dr. Stacey Ritz, Northern Ontario School of Medicine
Effect of metals present in particulate air pollution on the development of inhalation tolerance in mice

Most of the time when people inhale harmless substances, the immune system ‘trains’ itself to ignore them; this is called inhalation tolerance, and it is an important process that prevents unnecessary reactions in the lung that could be harmful. However, for some reason, some people do not develop inhalation tolerance and their immune systems respond to the harmless substances as if they were an infectious agent, resulting in diseases like hay fever and asthma. We know that some kinds of stimuli, like air pollution or cigarette smoke, can prevent the development of inhalation tolerance.

We want to find out whether the metals present in air pollution particles (such as nickel, copper, iron, and zinc) can cause the immune system to generate allergic responses against an otherwise harmless substance. There is an experimental system involving mice that mimics the process of inhalation tolerance in humans. In this study, genetically-identical lab mice are placed in a chamber where they breathe a mist containing a harmless protein, ovalbumin (OVA), for 20 minutes a day, for 10 days in a row. This procedure does not cause any apparent changes in the lungs of the mice, but it prevents them from being able to make any harmful responses to OVA in the future. We will test whether metals can affect this process by giving the mice a dose of the different metals 1 hour before they go into the chamber each day. We will then look at the lungs and blood of the mice to see if the metal treatment leads to any allergic-type responses.
We are focusing in on the metal components of air pollution because we believe they may be responsible for the ability of air pollution particles to trigger allergic immune responses to otherwise harmless substances. No one has previously examined this possibility.

Although we have significantly improved our ability to treat asthma and allergies, we still have a lot to learn about why they develop in the first place and how they could be prevented. If we are correct, and these metals are able to trigger immune responses to otherwise harmless substances, it would suggest that we might be able to improve the lung health of Canadians by more carefully regulating metal in air pollution emissions to try and reduce the development of asthma.

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Acute Lung Injury (ALI)

Dr. Claudia dos Santos, Saint Michael’s Hospital
Role of ATF3 and DJ-1 in myeloid and non-myeloid cells during ALI

In Canada, over 10,000 people die each year with acute respiratory distress syndrome (ARDS) the most severe form of acute lung injury (ALI). This condition is often lethal (35-65%), requiring admission to an intensive care unit (ICU) and mechanical ventilation (MV). The necessity for MV renders patients at risk for ventilator induced lung injury (VILI). Subsequent morbidity among survivors represents a significant burden of illness and cost to our health care system. Despite advances, no specific treatment exists. The only strategy demonstrated to reduce mortality relies on limiting MV to avoid lung stretch and consequent VILI.

With the support of the OTS we have identified two genes previously not known to be involved in ALI/VILI: (i) activating transcription factor 3 (ATF3) and more recently (ii) Parkinson disease (autosomal recessive, early onset) 7 (Park7 or DJ-1). Last year we received funding from OTS to study the role of ATF3 in lung injury. The data we have generated strongly suggest that ATF3 functions differently in lung resident versus inflammatory cells.In inflammatory cells ATF3 prevents “hyperinflammation” (i.e. over reaction to inflammation). In contrast, in lung resident cells, like epithelial cells, ATF3 promotes resistance to damage, that results in decreased lung edema (or fluid from entering air spaces). DJ-1 seems to be a key protein helping ATF3 to achieve its protective effects. How this happens is unclear. We are applying for a renewal of this grant so that we may investigate what are the molecular mechanisms that ATF3 uses to control inflammation and injury in different cell types, and how does DJ-1 help ATF3 to do this.

We will use a combined in-vitro and in-vivo approach. In vivo we have successfully generated the proposed ATF3 mice chimeras (“mixed” mice) that have ATF3 in either resident or inflammatory cells only. Studies using these mice have revealed how ATF3 may function differently in lung versus inflammatory cells. We now propose to use the material collected from these mice to assess for proteins known to be critically involved in lung edema formation and inflammatory cell trafficking and adhesion. In vitro we plan to use our adenovirus system that allows us to change the amount of ATF3 or DJ-1 in cells to study the role of ATF3 and DJ-1 in preventing loss of the ability of cells to act as a barrier. When “barrier function” is lost, fluid from vessels floods the lungs, preventing normal breathing. We also plan to isolate inflammatory cells from our gene deficient mice (DJ-1 and ATF3). We will then use these cells to study the role of ATF3 and DJ-1 in the migration (traffic of inflammatory cells) and adhesion (when inflammatory cells stick to sites of injury) of inflammatory cells.

Few groups work on trying to explain the combined effect of biochemical and biophysical injury in ALI/VILI. My laboratory uses state of the art genomic profiling to develop an “informed” (computational based) approach to the discovery of novel molecular targets for therapy. We use a multipronged translational strategy (multidisciplinary and multimodel) that includes microarrays, cell-based, gene deficient and chimeric animals. In fact our approach has yielded two new molecules not previously known to play a role in ALI/VILI. We also use this information to identify new drugs (Semapimod or CNI-1493) and genetics (adenovirus vectors) and fast track our findings to animal models to provide pre-clinical data on novel potential therapeutic strategies. If successful our viral-delivery approach can be used in future gene-therapy studies.

By 2026 an estimated ~34,000 Ontarians are expected to be on life support, many with ALI. The onus is on health professionals and scientists to come up with innovative approaches to reduce imminent morbidity and mortality. From a biological perspective ATF3 regulated the expression of hundreds of genes involved in the response to injury. DJ-1 modulates its function and has a significant impact on features of injury. Identifying strategies for early intervention will not only benefit ARDS patients, but also many other patients on life support.

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Dr. Anne Ellis, Queen’s University
Epigenetic Biomarkers of Atopy and Asthma at Birth

Asthma is a life-long breathing disorder, and there is no known cure. Many patients with asthma also have allergies but it is not known why some people develop asthma and others do not. A family history of allergies and maternal smoking are risk factors, but the association is never 100 percent. If we could understand how allergies develop, or predict the children who will be affected, we might be able to prevent or to reverse the process.

We inherit our genes from our parents, but we now know that there is more to genetics than just the DNA of the genes themselves. Inside our cells, our genes are covered in a knitted layer, like a sweater. This “clothing” on our genes controls when genes are turned on and off. When we inherit our genes from our parents, the clothing comes with it. But just like you can change your shirt, the clothing on our genes can also change when children are developing in the uterus, and throughout life. This “clothing” on the genes is called epigenetics. We think epigenetics might explain how allergies are passed on to children.
When babies are born, the umbilical cords are no longer needed. If it is okay with the mothers, we will take blood from the umbilical cord, and look at the “clothing” on their babies’ genes. We will also test the mothers for allergies. After one year and two years we will phone the mothers to find out if the babies have developed any symptoms of allergies or asthma, and they will have a chance to get their baby formally tested, if they wish. We will also look at environmental factors such as smoking status, and an estimate of the mother’s exposure to air pollution during pregnancy. We will compare the “clothing” on the genes of the babies who develop allergies or suspected asthma to those that did not. This way we will find epigenetic marks that might explain why some children get allergies and some do not, and how the environment might play a role.

Not much is known about how epigenetic marks might be related to the development of asthma/allergies in children. Learning which epigenetic marks are associated with asthma/allergies, and what environmental factors drive them, might help us prevent or cure the disease. Also, knowing which epigenetic marks in a baby’s cord blood can predict the development of asthma/allergies will help us develop a new test that could identify which children are at risk for asthma very early in life.

This project will help prevent allergic lung disease, as identifying new epigenetic markers of asthma at birth, may provide new therapeutic targets which may be able to prevent the development of asthma. We may also identify epigenetic markers that are indicators of infantile wheezing, and a higher risk of developing full-blown asthma later in life. Further research projects stemming from the current study may also be able to develop a test that can identify at birth which children will benefit the most from using inhaled corticosteroids for wheezing. The outcomes of this project will also help people manage lung disease and promote lung health, as an earlier test for asthma will help us to initiate asthma action plans for patients earlier.

Dr. Mark Inman, SJHH / McMaster University
Ozone-Facilitated Allergic Sensitization and Response

The number of people suffering from asthma and allergic diseases such as asthma is increasing in many developed and developing countries. One of the proposed reasons for this is that environmental factors such as pollution may increase the likelihood that individuals become allergic to essentially harmless substances such as house dust.

The objective of this project is to examine how on environmental product of pollution (ozone) can exaggerate the allergic response in mice. Of greater importance, we will explore the possibility that ozone can cause mice to become allergic to a level of allergen exposure that would not normally produce allergy.
We will use models of allergen and ozone exposure that have already been established in our laboratory. We will investigate whether the mice become allergic and develop signs of asthma using state-of-the-art tools already present in the laboratory.

The unique component of this project is that we will address whether the exposure to ozone can actually contribute to the cause of disease. Previous studies have focused on whether it can make established disease worse.

Clearly, greater understanding of the impact of environmental pollutants is essential to reformed control policies; this of paramount importance. We will also, however, investigate whether a class of therapy (anti-oxidant) can reduce the harmful effects of ozone exposure. This may translate into immediate health benefits to individuals currently exposed to unwanted environmental factors.

Dr. Helen Neighbour, McMaster University
Effect of allergen challenge on inflammation induced by toll-like receptor stimulation in a nasal model

Asthma is one of the most common diseases affecting about 2.5 million Canadians, and can result in reduced quality of life and difficulties with work and school. Once the disease has become established with irreversible changes in the lungs it can be very difficult to treat. Although less common than mild asthma, sever asthma uses more healthcare resources.

The objective of this project is to find out how the changes in the lung develop in severe asthma. Once this is known then new treatments can be developed to prevent irreversible damage to the lungs. Volunteers will have substances sprayed up their nose and then samples collected from their nose. Levels of proteins and cells can be measured in these samples. This will give an indication of the type of inflammation that occurs.

The usual method of investigating the changes that occur in asthma is to challenge the lungs. Samples have to then be collected from the lungs. This can be in the form of sputum which must be treated to break it down to a liquid or washed out during a camera test. These methods cause problems with measuring proteins and they are broken down or diluted. Because the nose is easily accessible samples can be obtained at many time points. Because the samples can be collected directly from the nose the problems with obtaining samples from the lung are avoided.

If the way in which the advanced changes that occur in asthma are worked out then new drugs could be developed to prevent them. With any disease it is important to prevent changes that cause worsening. The aim is to keep lungs healthy and to prevent severe, irreversible damage being done to the lungs in asthma.

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Dr. Luke Janssen, McMaster University
Calcium-Signaling and Gene Expression in Human Pulmonary Fibroblasts

One of the hallmarks of chronic lung diseases is the destruction of matrix, a structure critically important for the gas exchange function of the lungs. Fibroblasts are cells embedded in the matrix. In diseases such as fibrosis or chronic asthma there are too many of these cells in too much matrix; in emphysema there are not enough or they are distributed in an abnormal pattern. Beside the ability to produce matrix, fibroblasts are able to contract and influence tissue stiffness. Changes in ion concentration including calcium have marked effects on fibroblast function. We want to investigate if these ion alterations have a direct influence on the tissue strain and matrix composition in the lung, and if correcting abnormal calcium levels in or around fibroblasts have a beneficial effect on chronic lung disease.

Fibroblasts are the cells in the lungs which can either destroy lung tissue or create scar tissue which interferes with normal lung function. We would like to better understand how they work. We know that they have to express genes, and that gene expression in other cells is affected by a chemical change: a change in the concentration of calcium inside the cells. We also know that fibroblasts demonstrate very interesting calcium responses when they are stimulated. So we want to look at the relationship between changes in calcium inside the cells and gene expression.

We get human lung fibroblasts from lung tissues removed in operations. We can then pull out the fibroblasts and study them using our special microscopes (confocal, laser-illuminated, fluorimetric microscope) in order to see the changes in calcium under various experimental conditions. We can also look at how they express genes. We will therefore look at that gene expression under conditions in which calcium levels are changed. Very few people have looked at calcium responses in fibroblasts, and nobody world-wide has looked at the possibility that gene expression in fibroblasts might be affected by those calcium responses.
Fibroblasts play a very important role in both asthma and COPD: they cause changes in the structure of the lungs which lead to many of the consequences of those diseases. A better understanding of how they “work” could open the door to new drugs which would control what they do, and therefore help treat those diseases.

Dr. Diane Lougheed, Queen’s University
Physiology of Cough in Asthma: Comparison of Sensorymechanical Responses to Mannitol and High-dose Methacholine

Cough is a common, disruptive and at times disabling symptom which often prompts patients to seek medical attention. Determining the cause(s) of chronic cough can be challenging, and costly. Asthma and other airway disorders are among the most common causes of chronic cough. In addition, cough can be the only symptom of asthma. Little is known about why some patients with asthma primarily cough and do not develop the other symptoms of asthma such as shortness of breath or wheeze. Improved understanding of the reasons for these different manifestations may lead to new and more effective treatment strategies.
The purpose of this research is to better understand the mechanisms of cough in asthma and cough variant asthma, and to try to identify a fundamental difference in the mechanism between these two related conditions (called the ‘pathophysiology’).

This will be done by controlled testing in the laboratory of individuals with asthma and cough variant asthma. Study subjects will undergo 2 inhalation challenge tests on separate days (using mannitol and methacholine). These agents cause the airways to temporarily constrict (narrow) and simulate an asthma attack. We will record the type and severity of symptoms (shortness of breath and cough) and record pressures in their chest (using a special balloon catheter) and their lung function. In this way, we will be able to determine if their symptoms, particularly cough, relate to specific changes in lung function (such as air trapping).

This will be the first study to research the relationship between lung mechanics and pressure recordings and cough in asthma and cough variant asthma. We have noted that some individuals without regular asthma but with chronic cough trap air in their lungs similar to regular asthma, and this may be the stimulus for cough. Whether or not a deep breath can reverse the bronchoconstriction and relieve the air trapping may be the main difference between asthma and cough variant asthma, which has not been reported previously.

This research is directly in line with the Lung Association’s mission as it aims to improve the lung health and outcomes of individuals with asthma. By advancing our understanding of the mechanisms of cough in asthma and cough variant asthma, it may guide diagnostic approaches and inform future studies of therapeutic interventions in cough variant asthma. Ultimately, this may reduce morbidity from chronic cough and asthma.

Dr. Teresa To, The Hospital for Sick Children
Validation and use of evidence-based asthma care performance indicators in Ontario (VALUE-API)

Standard asthma-specific performance indicators, used to measure quality of care, have not been implemented and evaluated in Canada. In the past, single provincial health administrative data was used by researchers to calculate a small number of asthma performance indicators. These indicators have emphasized asthma medication use by patients while overlooking other elements that factor into quality asthma care, such as the use of spirometry for both diagnosing and ongoing monitoring of asthma, patient symptom control, asthma education, availability of an asthma action plan and unscheduled or urgent health services use due to asthma. A set of asthma performance indicators that measures aspects of primary care for asthma, such as prevention, health promotion, chronic care, health care provider interaction with patients, and health care provider collaboration with other health care sectors will be more useful for quality of care evaluation.

This proposed study will use evidence-based asthma indicators with standardized definitions (i.e. developed based on literature that showed supporting evidence for improved outcomes) to measure the appropriateness of asthma management, the effectiveness of asthma care, the accessibility of healthcare resources for individuals with asthma, and the overall wellbeing of people living with asthma.

To collect the data on quality of asthma care, we will combine a provincial health administrative data approach with collecting patient encounter data from primary care physician practices across Ontario. During or following a patient visit for asthma, primary care practitioners, (e.g. physicians, nurse practitioners, nurses, respiratory therapists, and asthma educators) in Ontario will participate by filling out either a paper, Adobe® PDF or web form documenting information on key asthma indicators (e.g. if the patient received spirometry in last 12 months or has received a written asthma action plan). Collecting this data will allow us to make appropriate comparisons amongst primary care practices and to generate more informative feedback.

The proposed study will be the first that collects provider-level and population-leveldata to evaluate a set of asthma indicators that was derived from published evidence. Results will address such issues as the relevance of the asthma indicators to primary care, their reliability in measuring clinical care or management, their responsiveness to change, and the feasibility of data collection. We will actively involve primary care providers in both the process of implementing the indicators and in evaluating them. The tested asthma indicators will provide a “set of tools” for performance and outcome measurement that allow for quality of care and services to be measured.

The outcomes of this project would be useful for those that need to decide where to start up asthma programs aimed at improving health outcomes and can also assist with evaluating how well a program has met its goals, whether it be to reduce hospital visits for asthma or increase the use of spirometry for diagnosis. This project will also provide a starting point for benchmarkingof asthma health care between practices across the province. Results will address issues about the asthma indicators related to their relevance to primary care, reliability in measuring clinical care or management, responsiveness to change, and the feasibility of data collection. It is important to provide meaningful information to those responsible for developing strategies to improve asthma care to the nearly 2.5 million Canadians living with the disease. Our results will help guide and evaluate these interventions and public policies aimed at improving asthma health in the population.

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Chronic Obstructive Pulmonary Disease (COPD)

Dr. Andrea Gershon, Sunnybrook Health Sciences Centre
Impact of pulmonary function testing on health outcomes of individuals with chronic obstructive pulmonary disease
*OLA/Pfizer Award

Chronic Obstructive Pulmonary Disease (COPD) is a common, progressive respiratory disease responsible for significant mortality and morbidity. The recommended approach to diagnosing COPD is by determining a patient’s symptoms and physical exam findings and then, very importantly, objectively assessing their lung function through breathing tests, also known as pulmonary function testing. Despite this scientific approach, however, there are many physicians who are satisfied making a ‘rough’ diagnosis of COPD without pulmonary function testing, as studies have found that only 30 to 50% of individuals with newly diagnosed COPD actually receive objective testing at time of diagnosis. It is not known if making an exact diagnosis of COPD (using pulmonary function testing) compared to making a rough diagnosis of COPD (without pulmonary function testing) has an effect on patient health outcomes. It has been presumed that a more exact diagnosis leads to better management and subsequently better health outcomes, like fewer hospitalizations, but this has never been confirmed. Therefore, we propose the current study to determine whether pulmonary function testing around the time of COPD diagnosis leads to better health outcomes like decreased hospital admission for people with COPD.

The objective of the study isto confirm that individuals with COPD who have had their diagnosis confirmed with objective pulmonary function testing have better long term health outcomes (like less hospitalizations) than individuals who have not.

Ontario health administrative data contains information on all the health care encounters (that are paid for by the government) of all people living in Ontario. We will use this data to divide all individuals with COPD living in Ontario, Canada into 2 groups based on whether or not they received pulmonary function testing around the time they were diagnosed. We will then look at and compare hospitalizations (and then emergency department visits and deaths) between these 2 groups to see if having pulmonary function testing has made a difference. Analytic techniques will be used to ensure that any differences found between the groups are due to pulmonary function testing and not other factors that could also influence these outcomes.

This study will be the first to look to see if pulmonary function testing leads to improvement in important patient outcomes like hospitalization for COPD. It will also use health information on every individual living in Ontario—a population of approximately 13 million—which is reflective of real world life and medical practise and therefore its results should very applicable to all the people living with COPD in Ontario.

The ultimate goal of health care providers and health care systems is to help patients lead longer and better quality lives and therefore demonstrating that pulmonary function testing improves the health of patients is very important. Patients want to undergo testing and procedures that improve their longevity and/or quality of life, busy clinicians want to provide quality care without wasting resources, governments and tax payers want to promote and pay for testing and procedures that have been proven to make a difference to peoples’ lives. Scientifically confirming that pulmonary function testing and the rigorous diagnosis of COPD improves peoples’ health will 1) validate the accepted practise of respiratory health care professionals, 2) help convince more physicians to use pulmonary function testing to objectively confirm COPD diagnoses in their patients, and 3) demonstrate the need for strategies to promote the more widespread use of pulmonary function testing to health care policy makers in government.

Dr. Roger Goldstein, West Park Healthcare Centre
A Randomized Controlled Trial of Balance Training in Individuals with COPD

Chronic obstructive pulmonary disease (COPD) is a common and costly condition in Canada and in the rest of the world. While treatment of patients with COPD is traditionally focused on the lungs, secondary impairments of the disease are now gaining more attention. A growing body of research shows that patients with COPD have important problems with balance control that may put them at a high risk of falls.

The goals of this research project are to develop a balance training program for patients with COPD who may be at risk of falling and to test the effects of this training program on measures of balance and fall risk. In the first part of the study, we will develop and pilot test a balance training program that targets some of the specific components of balance that are impaired in COPD. In the second part of the study, patients with COPD enrolled in respiratory rehabilitation will be randomly assigned to either a treatment or control group. Both groups will complete the standard 6-week program of rehabilitation that is well established at our centre. In addition to conventional respiratory rehabilitation, the treatment group will also complete a balance training program. The control group will receive general stretching and muscle relaxation exercises. Before and after completion of the program we will collect measures of balance and fall risk. These measurements will be compared between the treatment and control groups to determine the effects of the balance training program.
Despite the fact that patients with COPD have problems with their balance and are at an increased risk of falls, balance training and fall prevention programs are not identified in COPD management guidelines and therefore very few programs include any standardized balance assessment. This will be the first project to develop and evaluate a balance training program for patients with COPD.

The findings of the proposed research will help health care professionals better manage patients with COPD by assessing those at high risk for falls and implementing balance training programs designed to reduce fall risk. Given the devastating consequences of falls in older adults, this research has important implications for the functional independence and quality of life of individuals living with lung disease.

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Lung Disease

Dr. Indra Narang, The Hospital for Sick Children
Opioid-induced Respiratory Depression in Children

Opioid drugs such as morphine or fentanyl are frequently administered to children to alleviate pain, but lead to opioid-induced respiratory depression. Newborns with an immature respiratory system are one of the highest risk groups for both irregular breathing and sleep-disordered breathing such as pauses in breathing known as apneas. Newborns often require invasive procedures and, despite their unstable breathing, need opioid analgesics to alleviate pain. Opioid analgesics are also the first line of analgesia in older children following elective surgery. In the post-operative period, medical concern for opioid-induced respiratory depression is such that provision of effective analgesia may be suboptimal, with particular concern for the nighttime period when the stimulating effects of wakefulness on respiration are withdrawn. Yet, the effects of opioid analgesics on breathing in newborns and children, especially during sleep, have not been studied to identify the factors contributing to opioid-related respiratory depression and the magnitude of attendant risks.

We will evaluate the impact of opioid analgesics on breathing across sleep-wake states and will determine whether opioid analgesics promote an increase in apneas. We propose to study two groups of children at different ages: infants (from prematurity to 6 months-old) and children aged 2-10 years. We will establish whether (1) opioid analgesics induce respiratory depression and promote sleep-disordered breathing, whether (2) young infants exhibit more severe respiratory depression in response to opioids compared to older children, and whether (3) opioid-induced respiratory depression is exacerbated in sleep.

Sleep, respiratory activity, and sleep-disordered breathing (such as central and obstructive sleep apneas) are all evaluated by a sleep study known as polysomnography before and after administration of the opioid analgesic morphine in children for medical reasons at the Hospital for Sick Children in Toronto.
This project will study for the first time the factors contributing to the severity of opioid-induced respiratory depression in children. Because of their immaturity, children, and especially young infants, present unstable breathing and are highly sensitive to opioid analgesics. This project will establish whether the immaturity of the respiratory system contributes to the severity of respiratory depression and to the occurrence of sleep disordered breathing by comparing the sensitivities to opioids of two distinct groups of children at different ages. This project will determine whether sleep aggravates respiratory depression by opioid analgesics, which is of particular concern given that patients who receive opioid analgesics during the post-operative period spend a significant amount of time asleep.

According to the Canadian Thoracic Society guidelines, post-operative medications such as opioid analgesics increase the severity of obstructive sleep apneas. However, little is known about the mechanisms mediating the increased severity of breathing disorders due to opioids, especially in children who present an immature respiratory system. Understanding the mechanisms and factors pertaining to opioid-induced respiratory depression in children is crucial to develop new therapeutic strategies to reduce and/or prevent opioid-induced respiratory depression.

Dr. Neil Sweezey, The Hospital for Sick Children
Regulation of Perinatal Lung Development by Glucocorticoid Responsive Signaling 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 signaling) that improve lung function in BPD, but bad effects of steroids on newborn brain and lung mean that they are no longer used for treatment of this condition.

Since there is still no safe and effective therapy 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 steroids themselves.
It has been assumed that glucocorticoid signaling needed for lung development is present in the type of lung cells called mesenchyme. We plan to use mice genetically engineered to lack glucocorticoid signaling in mesenchyme to help us identify which biological messengers (genetic signals) in this cell type are involved in lung development. We will compare genetic signals in these mice with those in normal mice.
Our mice were genetically engineered for the purpose of doing this study. We are not aware of anyone else who has such mice 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). We expect that the results of this project will help us find natural biological messengers 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.

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Pulmonary Arterial Hypertension

Dr. Roma Sehmi, McMaster University
Role of vascular endothelial progenitor cells in lung angiogenesis
*OLA/Pfizer Award

When you cannot breathe, nothing else matters. Asthma is a chronic disease of the airways that affects more that 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 using a mouse model of asthma.

Using a mouse model to mimic the changes that take place as asthma develops in humans; we will study the role that immature or precursor cells from the bone marrow play in the development of new blood vessels once they reach the lungs. By giving a specific drug that inhibits the movement of the precursor cells to the lungs, we will investigate how important these immature or precursor cells are for the formation of new blood vessels in the lungs. In addition, we will determine whether stopping their movement to the lungs has any effect on the vessel formation and other asthma symptoms.

In the current study, we will use mice that lack one very important cell that contributes to asthma diseases, namely eosinophils. These cells increase in the lungs in great numbers during an allergic response and the products of these cells have been shown to cause many of the changes in the lungs observed in asthma. The aim of these experiments will be to investigate whether eosinophils are at all involved in the recruiting the immature precursor cells from the bone marrow to the lungs in an asthmatic response. This will determine whether increased blood vessel formation in the asthmatic lung is an independent process to the recruitment of eosinophils. If so, then directly controlling this process may have additional benefits in the treatment of asthma.

Increased formation of blood vessels is a prominent feature of the asthmatic lung and studies have shown that it 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.

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Sleep Disorders

Dr. Clodagh Ryan, UHN/Toronto General Hospital
Spatial and Temporal Patterns of Cerebrovascular Response to Hypercapnic Stimuli in Subjects with, and without, Obstructive Sleep Apnea (OSA)
**Breathe New Life Award

Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder in the general population in which recurrent collapse of the upper airway occurs during sleep. OSA is more prevalent in subjects with stroke and is associated with a 3 fold increased risk of stroke. This makes it a serious public health problem. Approximately 50% of subjects with OSA are asymptomatic and are often only detected following investigation for the cause of heart disease or a stroke. In subjects who are treated for OSA many are intolerant or poorly compliant with treatment. Therefore, the identification of those subjects with OSA most at risk of adverse consequences such as stroke is important, so that treatment compliance can be improved.

To determine if compared to subjects without OSA, subjects with OSA have evidence of increased stroke risk by assessment of changes in cerebral blood flow (cerebrovascular reactivity) as measured on Doppler ultrasound of the middle cerebral artery (TCD) and blood oxygen level dependent magnetic resonance imaging of patterns of cerebral blood flow (BOLD MRI) to increased carbon dioxide concentrations (causes increased cerebral blood flow). In order to deliver this stimulus we will use a special machine (RespiractTM) which allows for the precise control of carbon dioxide and oxygen concentrations in the lungs and blood. The precise control of carbon dioxide and oxygen in conjunction with BOLD MRI will allow the production of detailed maps of the brain that identify areas of healthy and abnormal blood supply.

Subjects both with and without untreated OSA matched for age, sex and body mass index will be recruited. They will have cerebrovascular reactivity measured by transcranial Doppler the night before and the morning after an overnight sleep study. At a later time point they will have BOLD MRI performed with mapping of the cerebrovascular reactivity.

Our study is the first study to examine circadian patterns of cerebrovascular reactivity in OSA subjects compared to controls. Secondly, our study will be the first study to examine cerebrovascular reactivity using BOLD MRI mapping in subjects both with and without OSA.

Obstructive Sleep Apnea (OSA) is a prevalent sleep-breathing disorder in the general community. In view of the associated increased mortality and morbidity from stroke in OSA subjects, it is important to identify those subjects with OSA who are most at risk. This study may allow longer term identification of subjects with OSA who are most at risk of stroke by evaluating changes in cerebral blood flow responses on BOLD MRI.

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Smoking Cessation

Dr. Christian Hendershot, Centre for Addiction and Mental Health
Prazosin as a Novel Treatment for Smoking Cessation

Cigarette smoking is the leading preventable cause of mortality worldwide and contributes to substantial economic and health burdens in Canada. Smoking among Canadians accounted for an estimated $17 billion in health care costs and over 37,000 deaths in 2002. Eighteen percent of Canadians ages 15 and older are current smokers, of which 77% are daily smokers. Despite the availability of pharmacological and behavioural interventions, only a minute proportion of smokers quit each year and the vast majority of quit attempts result in relapse. It is therefore critical to continue to advance novel smoking cessation treatments.

Recent evidence suggests that the α1-adrenergic receptor antagonist prazosin, a safe and effective medication for hypertension, reduces nicotine self-administration and relapse in animal models of nicotine dependence. Additionally, recent findings suggest that prazosin is a potentially effective treatment for alcohol dependence in humans. However, data on prazosin for smoking cessation in humans is currently lacking. The goal of this project is to provide an initial evaluation of prazosin as a novel medication for smoking cessation.

A randomized medication screening trial will be conducted at the Centre for Addiction and Mental Health. Adult smokers who report motivation for quitting will participate in a study involving two brief simulated quit attempts (16 mg/day prazosin versus placebo). During quit attempts participants will complete daily measures of smoking, craving, withdrawal, and medication adherence. Additionally, participants will complete experimental sessions during medication and placebo conditions to evaluate medication effects on laboratory-based measures of nicotine-related behaviour and reward.

Although animal studies show that prazosin reduces nicotine-seeking behaviour, there are currently no published studies examining prazosin as a treatment for nicotine dependence in humans. This study will be among the first to address this question. Additionally, the study design will incorporate methods from both controlled laboratory research and clinical trials. This combination of approaches will result in a medication screening trial that is relatively rigorous but also brief, cost-efficient and inclusive of clinically relevant outcomes.

Cigarette smoking is the chief cause of lung disease and the leading cause of preventable mortality in Canada and worldwide. The proposed research will provide among the first data on the efficacy of prazosin for smoking cessation. Specifically, the current study will inform whether prazosin should be tested in larger clinical trials of smoking cessation. If prazosin proves useful for facilitating smoking cessation and/or reducing relapse, the proposed research could lead to improved 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 requests totaling $1.7 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. Claudia dDs Santos, St. Michael’s $49,000
Role of ATF3 and DJ-1 in myeloid and non-myeoid cells during ALI
Dr. Anne Ellis, Queen’s University $37,751
Epigenetic Biomarkers of Atropy and Asthma at Birth
** OLA/Pfizer Award Recipient
Dr. Andrea Gershon, Sunnybrook Health Sciences $50,000
Impact of Pulmonary Function Testing on Health Outcomes of Individuals with Chronic
Obstructive Pulmonary Disease
Dr. Roger Goldstein, West Park Healthcare Centre/University of Toronto $46,558
A Randomized Controlled Trial of Balance training in Individuals with COPD
Dr. Christian Hendershot, Centre for Addiction and Mental Health/University of Toronto $42,500
Prazosin as a Novel treatment for Smoking Cessation
Dr. Mark Inman, St. Joseph’s Healthcare Hamilton/McMaster University $43,163
Ozone-Facilitated Allergic Sensitization and Response
Dr. Luke Janssen, McMaster University $49,000
Calcium-Signalling and Gene Expression in Human Pulmonary Fibroblasts
Dr. Diane Lougheed, Queen’s University $49,000
Physiology of Cough in Asthma: Comparison of Sensory-mechanical Responses to Mannitol and High Dose Methacholine
Dr. Indra Narang, Hospital for Sick Children $47,961
Opoid-Induced Respiratory Depression in Children
Dr. Helen Neighbour, McMaster University $45,240
 Effect on Allergen Challenge on Inflammation Induced by Toll-Like Receptor Stimulation in a Nasal Model
Dr. Stacey Ritz, Northern Ontario School of Medicine $48,930
Effect of Metals Present in Particulate Air Pollution on the Development of Inhalation Tolerance in Mice
* Breathe New Life Award recipient 2011-2012:
Dr. Clodagh Ryan, University of Toronto/ Toronto General Hospital/UHN $50,000
Spatial and Temporal Patterns of Cerebrovascular response to hypercapnic stimuli in
subjects ith, and without, Obstructive Sleep Apnea
** OLA/Pfizer Award Recipient
Dr. Roma Sehmi, Firestone Institute for Respiratory Health/ McMaster University $50,000
Role of Vascular Endothelial Progenitor Cells in Lung Angiogenesis
Dr. Jeremy Simpson, University of Guelph $49,000
Mechanisms of Diaphragmatic Dysfunction Induced by Heart Failure with Myostatin Inhibition for Therapeutic Translation
Dr. Neil Sweezey, Hospital for Sick Children $48,972
Regulation of Perinatal Lung Development by Glucocorticoid  Responsive Signalling in Mesenchymal Cells In Vivo
Dr. Teresa To, Hospital for Sick Children $48,721
Validation and Use of Evidence-based Asthma Care Performance Indicators in Ontario (VALUE-API)


*   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 COPD and Pulmonary Arterial Hypertension, respectively.

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