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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 15 projects funded by the Lung Association during the 2010-2011 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.
Dr. Claudia dos Santos, Saint Michael’s Hospital
ATF3-dependent Molecular Pathways of Injury and Repair in Lung Injury
Acute respiratory distress syndrome (ARDS) is a catastrophic form of acute lung injury (ALI) that occurs as a consequence of sepsis, aspiration, trauma or infection with viruses such as the severe acute respiratory syndrome (SARS), H5N1 (avian) and H1N1 (swine) flu virus. In Canada, over 10,000 people die each year with ARDS. Despite advances in ICU care, the mortality from ALI/ARDS is still close to 50%. Many patients are so sick they need to be on mechanical ventilation. However, mechanical ventilation itself may result in ventilator induced lung injury (VILI). Lung stretch due to cyclic stretching can increase mortality by nearly 10%. Currently there are no pharmacological therapies for ALI/ARDS or VILI, hence treatment is entirely supportive. Reducing the volume of air used to inflate the lung is the only strategy shown to decrease mortality, but this is not always feasible in very sick patients. Accordingly, understanding the molecular basis for lung injury and repair is of high priority if we are to find new treatments.
With the support of the Ontario Thoracic Society/The Lung Association, Dr. dos Santos’ lab has indentified a transcription factor (a protein that works in the nucleus to regulate the production of various other genes) activating transcription factor 3 (ATF3) as a key regulator of the response to lung injury. This gene protects cells from injury and inflammation—this is known because genetically manipulated mice, which do not have ATF3, are much more susceptible to lung injury than wild type animals where the gene is intact. In our studies, it seems that ATF3 suppresses or inhibits the production of important “bad” mediators that are responsible for injury and inflammation. In addition, ATF3 also seems to enhance “good” mechanisms that protect lung cells from injury – little is known about these “good” mechanisms of defence. Determining how ATF3 confers protection to lung injury is the primary topic of this study. The researchers will use a combined in-vitro and in-vivo approach. In-vitro, they will manipulate ATF3 expression using an adenovirus system, which will allow them to change the amount of ATF3 in lung cells and determine the effects this has on mechanisms of protection from cyclic stretch or/and lipopolysaccharide (a component of bacteria associated with “bad” infection). To understand how these mechanisms play a role in ALI/VILI in-vivo, they have developed ATF3 mice chimeras, which are “mixed” mice composed of two genetically distinct types of cells. In chimeras, the bone marrow (BM) is eradicated and replaced with cells from a different mouse strain, enabling the researchers to define the role of ATF3 in different cells during lung injury in-vivo.
This study has shed new light onto two previously unrecognized mechanisms by which VILI may induce injury and the researchers are using this information to identify novel pharmacological (Resveratrol and Semapimod) and genetic (ATF3 gene delivery) therapeutic strategies for the treatment of ALI/VILI.e). From a biological point of view, ATF3 functions at a fundamental level to regulate the expression of hundreds of genes and modulate the inflammatory and immune response in the lung – the impact of alterations in ATF3 are of clinical relevance. Understanding how protection from CS and VILI occurs is timely and will provide new insights into which pathways or/and molecules may serve as novel therapeutic targets. Moreover, identifying strategies for early intervention will benefit not only ARDS patients, but perhaps many patients on life support, when the injury is known to begin with intubation.
Dr. Wolfgang M. Kuebler, St. Michael’s Hospital
Angiotensin–(1-7) signaling via the Mas receptor constitutes an intrinsic protective pathway and a novel therapeutic strategy in acute lung injury
Acute lung injury (ALI) is a disease in which lungs fail to take up oxygen. This will limit normal function and survival of our body. In North America, ALI is the major cause of death in critical care. The disease develops fast and can be triggered by other diseases or incidents. There is currently no drug for the therapy of ALI.
The renin-angiotensin system (RAS) consists of a series of small molecules. They are formed one from another by specific proteins called enzymes. At the end of the cascade is the small molecule angiotensin II (AngII). The binding of AngII to its receptor AT1 is important for the regulation of blood pressure. Recently, we learnt that the RAS is also important in ALI. It was shown that a specific enzyme, ACE2, protects mice from ALI. ACE2 degrades AngII to the small molecule Ang-(1-7). The authors suggested that AngII binding to AT1 promotes lung injury. Hence, AT1 receptor blockers may be promising drugs in ALI.
Yet, there is an alternative explanation possible. ACE2 not only degrades AngII, but also forms Ang-(1-7). Ang-(1-7) is protective in diseases of the heart and blood vessels. It binds to its receptor Mas and opposes the effects of AngII. We therefore propose that Ang-(1-7) may contribute to the protective effect of ACE2 in ALI. In pilot experiments, we could show that Ang-(1-7) is protective in ALI. This suggests that Ang-(1-7) and Mas present excellent targets for the treatment of ALI in patients. Here, we aim to consolidate this notion. We also aim to study the mechanisms by which Ang-(1-7) protects lungs.
First, Dr. Kuebler will establish the best dose for the treatment of ALI by Ang-(1-7). Then, his team will test whether the same effect can be achieved by an Ang-(1-7) mimic that can be taken orally. Next, they will test whether inhalation of Ang-(1-7) may increase lung protection and reduce side effects. Dr. Kuebler’s lab will then study whether the effect of Ang-(1-7) is caused via its receptor Mas. They will also test whether other drugs in fact confer protection by stimulating Mas. They will examine the mechanism by which Ang-(1-7) may protect lungs. Dr. Kueber’s study will focus on two mechanisms: Does Ang-(1-7) increase the production of a small gaseous molecule, nitric oxide? Does Ang-(1-7) inhibit platelets, small blood cells that contribute to ALI?
Due to the lack of therapies, ALI is a big problem in critical care. Dr. Kuebler proposes a new hypothesis for the treatment of ALI. The small molecule Ang-(1-7) which is produced by the body itself may protect lungs. This idea constitutes a new mechanism. It provides new insights into process causing ALI. Importantly, Ang-(1-7) and its receptor Mas present new targets for the treatment of ALI.
ALI is the main cause of death in critical care in Canada. The lack of drug treatment for ALI makes this disease particularly devastating. We aim to identify new targets and drugs that can protect the lung. Our strategy is based on a biological signaling process that is a natural protective regulator against ALI. Mimics of these signaling molecules can be orally administered. They could soon be introduced into the clinical scenario to treat ALI and thus, improve lung health.
Dr. Ruud Veldhuizen, The University of Western Ontario
Mechanisms of surfactant function and dysfunction
Acute lung injury (ALI) is a condition of severe lung dysfunction that can occur in people of all ages. These patients are cared for in the intensive care unit of the hospital. Beside supportive treatment and allowing the person to recover, there is currently no known treatment for ALI.
Dr. Veldhuizen’s interest is in a treatment approach called exogenous surfactant therapy. There have been extensive laboratory studies suggesting that this treatment would have a benefit in patients with ALI, however when tried in the clinical situation the treatment did not appear to be advantageous. The objective of this lab is to improve this treatment approach. The first step to do this is to understand what happens to the administered drug (i.e. surfactant) immediately after the treatment.
The researchers utilize adult rats in which the disease and treatment that occurs in patients with ALI are mimicked. Following induction of ALI and surfactant treatment, they will monitor the animal to determine the response to treatment. Subsequently, they will recover the surfactant and analyze it function to elucidate if and how this material has been inactivated.
The strength of this study is that it combines animal work that mimics a clinical problem with extensive laboratory analysis of the surfactant system. To our knowledge there are no other laboratories in the world that can combine these technological approaches.
The mortality rate of ALI in Canada and the rest of the western world is in the range of 30- 60%. By understanding the mechanisms that influence the efficacy of surfactant treatment approaches we generate optimal surfactant preparation that will ultimately reduce the mortality of this condition.
Dr. Cory M. Yamashita, Lawson Health Research Institute
The Role of Matrix Metalloproteinase-3 in Acute Lung Injury and Multiple Organ Failure
Each year, thousands of Canadians sustain a severe injury to the lung, such as severe pneumonia, that results in a process of rapidly progressive inflammation, known as the acute respiratory distress syndrome (ARDS). It has been estimated that the cost associated with a single patient admission to hospital with ARDS approaches $15,000, putting the national expenditure for this condition at over 2 billion dollars annually. This syndrome is characterized by an insult to the lung leading to a rapid onset of respiratory failure associated with low blood oxygen levels. Patients typically require admission to an intensive care unit for mechanical ventilation, or artificial breathing assistance, in order to survive the initial injury. Despite optimal medical treatment however, 30-50% of these patients will ultimately die in hospital due to this illness.
The majority of patients succumb to this illness as a result of damage to other organs, such as the liver, kidneys and heart, known as multiple organ failure (MOF). The specific reason for this phenomenon, and the reasons for which MOF develops in the context of ARDS, are currently unknown. An attempt to gain a greater understanding of the mechanisms by which MOF develops in the context of ARDS will be the central focus of this study.
Researchers speculates that harmful mediators are released by the lung into the bloodstream upon a severe insult, and subsequently these mediators circulate downstream where they have the propensity to induce damage in peripheral organs. Dr. Dr. Yamashita’s research will focus on a specific enzyme, matrix metalloproteinase-3, which we have determined to be released into the circulation by the lung in response to injury. Herein, a multidisciplinary approach will be used to advance this primary observation. Animal models of lung injury will be employed and blood samples from patients with ARDS will be obtained to confirm our preliminary findings that MMP-3 can be released directly from the lung into the systemic circulation in response to injury. Subsequently, in vitro cell culture techniques will be used to assess the effects of MMP-3 on peripheral organ function. The proposed series of experiments will attempt to establish a definitive link between the injured lung and the initiation of MOF by implicating MMP-3 as a key mediator of these events.
This line of investigation represents a novel approach to address the current reality that new and effective treatments are urgently required for these patients in whom the mortality remains unacceptably high. Any new discoveries in ARDS pathogenesis which may potentially lead to the development of new therapeutic options for this disease would be a significant contribution toward improving the lung health of patients affected by this syndrome. This study attempts to challenge the current disease paradigm by shifting the focus away from conventional treatment principles which have focused almost exclusively on lung-based targets, toward a strategy which addresses the systemic repercussions of multiple organ failure.
This research has widespread implication for the “lung health” of the thousands of Canadians who are affected by ARDS each year, and this has become distinctly evident in light of the recent H1N1 influenza outbreak. Beyond the development of effective treatment options, events such as these have exposed our limited understanding of the mechanisms which underpin these processes despite years of intensive investigation. It will be through a greater understanding of the molecular pathways which define these illnesses, some of which are addressed in this study, that these challenges may be met.
Dr. Mark Larché, McMaster University
The role of allergen-induced inflammation in the development of chronic airway hyperresponsiveness (AHR)
Asthma is a major cause of ill health and death. Furthermore, asthma represents a major economic burden through cost of treatment, drugs and lost days of work and schooling. Asthma is a chronic (long-term) disease that includes “inflammation” which can be thought of as a “fire within the lungs”. The “fire” can be treated with drugs like steroids. Asthmatic patients also commonly have “scarring” of their lungs and they often have very “twitchy” lungs that can close-up quickly if they breathe in allergens like grass pollen, or house dust mites, or cold air or air pollutants. Researchers refer to the twitchiness as “AHR” (airway hyperresponsiveness), and believe that it may be the result of the scarring of the lungs that is seen in asthma.
To test whether a vaccine for allergies and asthma that is being developed to treat patients, can prevent the scarring and twitchiness seen in the lungs of asthmatic patients, Dr. Larché’s lab will test the vaccine in a “mouse model” of asthma to answer this question quickly and cheaply. They will use two existing mouse models of asthma in order to treat house dust mite (HDM)-allergic mice, which are also exposed to HDM every few days for several months, with the vaccine.
The unique and innovative elements of this project are that he is testing components of a vaccine that is being developed for use in humans with allergies and asthma. The vaccine is in advanced clinical trials in Canada right now. Dr. Larché’s and his team’s project is the first to test such a vaccine in mice that have scarred and twitchy lungs as a result of their asthma. Scarring and twitchiness are major features of asthma and account for a large proportion of the disease burden. They will test the potential clinical value of this treatment approach in preventing and/or improving aspects of chronic asthma like scarring and twitchiness that are not effectively treated with currently used drugs.
Dr. Larché has spent the last 15 years developing and testing vaccines for asthma and allergic diseases. These “therapeutic vaccines” for the treatment of established disease are now being evaluated in a series of clinical trials in allergic subjects. Results to date are encouraging and it is hoped that the first of these vaccines will be approved by regulatory authorities in the next 3 years. These vaccines are “curative” or “diseasemodifying” and do not simply treat symptoms like most of the currently available approaches. This funding application addresses how effective these vaccines will be in preventing or reversing chronic asthma outcomes such as airway twitchiness (AHR) and scarring (airway remodelling). If they are successful, they will not only help patients manage their asthma, but they may prevent patients with mild disease progressing to more severe disease and even prevent individuals with rhinitis going on to develop asthma. The clinical trials are all being performed in Canada and Canada is currently the first target territory for regulatory approval.
Dr. Smita Pakhale, The Ottawa Hospital Research Institute
A randomized Control Trial of Weight Reduction in Obese Patients with Bronchial Asthma
Obesity is increasing dramatically not just in North America and Europe but also in low- and middle-income countries. Studies have shown that obese people are twice as likely to be diagnosed with asthma. Hence, there is growing interest amongst researchers to study links between asthma and obesity. Does obesity puts you at high risk of getting asthma? Or, is it the other way around: if you have asthma, perhaps you have a greater tendency to become obese? This dilemma has not yet been solved and researchers around the world are struggling to find an answer. Though there is growing support that obesity might put you at high risk of developing asthma, we do not know how. There are a lot of confusing issues around this. Obese people do have more difficulty breathing, they can not exercise as much as normal weight people, and they have more ‘indigestion’ symptoms. Do all these symptoms put obese people at high risk of being ‘labeled’ as asthma? Or, do they really have more asthma than normal weight people. Unless we develop well thought out research projects we will not find out answers to all these very important questions. Hence, we have planned a study of obese individuals with asthma.
The main objective of our study is to find out if weight reduction reduces the severity of asthma in obese asthmatic subjects. We will first confirm the diagnosis of asthma in our laboratory with simple breathing tests. Then those eligible for the study will be randomly divided in to two groups. One group will be enrolled in a state-of-art, structured weight reduction program for 3 months at the well known Weight Management Clinic at the Ottawa Hospital, Civic Campus. The other group will receive the current standard of care of asthma. Both the groups will get equal attention during the three months as we will follow them monthly. At the end of the 3 months we will analyze our data. We expect to see the group of subjects in the structured weight reduction program will have a weight loss of average 20 kg. If weight loss improves asthma control then we would expect that this group will have less severe asthma and bronchial hyper-reactivity, better lung function and improved quality of life at the end of 3 months.
This study will prove that weight reduction make you feel better not only because your lung function is better but also because in fact weight loss makes your asthma better. It has not yet been shown that weight reduction has an impact on asthma severity per say. If this is indeed the case, we can design very effective, economical community-based weight management programs catering to the population at risk. This in turn will benefit obese asthmatic and allow them to feel better and less severe asthma; which will reduce health-care cost by having not to go to emergency room or to get hospitalized for asthma attacks as frequently as before. Saving much needed health care dollars will be one amongst many long term benefits of this study.
Dr. Denis E. O’Donnell, Queen’s University
Pathophysiological Mechanisms of Dyspnea and Exercise Intolerance in GOLD Stage I COPD: Comparison of Symptomatic and Asymptomatic Patients
Chronic Obstructive Pulmonary Disease (COPD) is a growing cause of death, disability and health care costs in Canada. Nevertheless, COPD remains largely under-diagnosed and under-treated, particularly in its early stages. Patients with mild COPD have variable respiratory symptoms and often go unrecognized by their caregivers. However, recent studies indicate that symptomatic smokers with near normal breathing test results can have extensive small airway damage and are limited in their ability to undertake physical activity.
The objective of this study is to better understand the mechanism(s) of respiratory symptoms and activity-limitation in a group of mild COPD patients whose respiratory symptoms vary from none at all to troublesome breathlessness requiring medication. Dr. O’Donnell’s lab will compare detailed tests of small airway function (airway closure, abnormal distribution of ventilation and lung overinflation) and conduct a thorough evaluation of several key physiological parameters during exercise in symptomatic and asymptomatic patients with mild COPD. The researchers will test the hypothesis that patients with the most intense breathlessness during physical exertion will show greater abnormalities of small airway function and the greatest disharmony between the increased central neural drive to breathe and the ability of the respiratory system to meet this demand.
This will be the first study to characterize in a very comprehensive manner the nature and clinical consequences of the physiological impairment that exists in smokers with apparently mild airway obstruction. This novel information becomes critical if new diagnostic tests are to be developed for early COPD and is the first step in refining treatments to improve the quality of life of these individuals.
A better understanding of the nature of the respiratory impairment in smokers with earlier COPD, and the identification of the best pulmonary function test to predict the presence of respiratory symptoms is urgently needed. This research project fully fulfills the mandate of the Canadian Lung Association and Canadian Thoracic Society in their mission of improving the lung health of Canadians.
Dr. Dawn M.E. Bowdish, McMaster University
Macrophage scavenger receptors – novel recognition receptors for Mycobacterium tuberculosis
Over one third of the world’s population is infected with Mycobacterium tuberculosis, a tuberculosis-causing bacteria, and 10% of those infected will go on to develop the active disease. Although uncommon in Canada, Canadians cannot afford to be unconcerned since international travel has brought drug resistant strains within our borders. In order to be cured of M. tuberculosis, months of antibiotic therapy with substantial side effects are required. The current antibacterial treatments are ineffective against drug resistant strains.
For the discovery of new treatment, it is important to understand how M. tuberculosis destroys the host’s immune response. The M. tuberculosis infects macrophages, the sentinel cells of the immune response, whereas most pathogens try to avoid being recognized and “eaten” (phagocytosed) by macrophages. The tuberculosis causing bacteriarequires ingestion and lives inside the very cells that should destroy it. Ingestion occurs through a number of surface expressed proteins (receptors) on macrophages. Dr. Bowdish’s lab has discovered a macrophage receptor called MARCO that is associated with ingestion and pro-inflammatory responses to M. tuberculosis. In addition they have also discovered that subtle genetic variations within the gene that encodes this receptor predisposes an individual to infection with tuberculosis.
The objective now is to discover how M. tuberculosis interacts with macrophages and specifically this macrophage receptor in order to determine if it is a target for new drug therapies. A mouse model of infection will be used in order to understand how this receptor contributes to host defence against M. tuberculosis. The mice are defective in MARCO expression (i.e. MARCO “knockouts”), which allows us to determine if they are unable to properly respond to infection. Unique tools such as the MARCO knockouts, macrophage specific reagents and state-of-the-art equipment allow this research to rapidly progress on determining the relevance of this receptor in infection. The long term aim of this project is to discover new treatments for tuberculosis, especially drug resistant strains of tuberculosis, that work not by killing the bacteria directly, as conventional antibiotics do, but rather by stimulating host immunity.
Dr. Manel Jordana, McMaster University
Impact of flu infections on allergen responsiveness during immune development
Allergic asthma is a chronic immune-driven disease that is characterized clinically by reversible airflow obstruction and hyperreactive airways. In fact, it is the most common chronic disease in children. Allergic asthma typically occurs as a consequence of exposure to common aeroallergens. The most important indoor aeroallergen is house dust mite (HDM). A hallmark of allergic asthma is inflammation of the airways. There are different types of cells that comprise asthmatic inflammation. These cells can produce many different molecules that can either damage the airway or perpetuate the inflammatory reaction. Importantly, the sustained presence of inflammation around the airways leads to changes in their structure, a process referred to as remodeling. It is thought that these changes are important because they impair the function of the airway and, hence, contribute to clinical symptoms. Even though we have learned a great deal about these processes, how asthma develops especially in early childhood remains largely unknown.
Since the prevalence of asthma has risen dramatically over the past 3-4 decades, it is unlikely that this increase is attributable to a population-wide genetic shift. Instead, exposure to environmental factors, such as viral infections, may influence the development of allergic sensitization and asthma, particularly in the very young. Exposure to viral infections may alter the context in which the immune system “sees” aeroallergens in such a way as to facilitate immunological responsiveness and initiate processes that will lead to allergic disease. That allergic asthma commonly develops in children underscores the importance of these environmental influences in early life. This study seeks to investigate the impact respiratory viral infections have on responsiveness to HDM in early life, advance some mechanisms and evaluate the long-term consequences of viral-allergen interactions in terms of both function and structure of the airways.
To address these questions, Dr. Jordana’s lab will use a mouse model of HDM-induced allergic asthma that we have developed and extensively characterized. In addition, they will use a mouse model of influenza A (flu) infection that we have established, and published on, in our laboratory. Thus, neonatal mice will be infected with flu and during the course of acute flu-induced airway/lung inflammation will be exposed to the aeroallergen HDM. The researchers will investigate for evidence of allergic sensitization (i.e. becoming atopic) and allergic airway/lung inflammation. They will also determine the impact that this co-exposure has on the function of the airways. Lastly, the long-term consequences of this process on the airway structure, i.e. remodelling, will also be evaluated and see if these probable changes are permanent.
The questions asked in this research proposal are very important to determining the origins of asthma. Understanding the mechanisms underlying the development of asthma, particularly in early life, is fully in line with the mission of the Lung Association. In addition, the researchers believe that the study has potential implications for the management of allergic asthma, particularly in children.
Dr. Warren L. Lee, University of Toronto
Influenza infection of human endothelium leads to microvascular leak: cellular and molecular mechanisms
Breathe New Life Award 2010-2011
The influenza virus causes hundreds of thousands of deaths annually. Because it is prone to genetic mutations, new strains of the virus are capable of fooling vaccines and developing resistance to medications. In the most severe cases, patients with influenza can develop damage in the lung, leading to leakage of fluid out of the blood vessels and into the lung. This complication makes it difficult to breathe, and is associated with a 40% mortality rate. The influenza virus is already known to infect certain types of cells in the lung known as epithelial cells. However, all blood vessels in the body, including those in the lung, are lined with another type of cell known as endothelium. One of the main functions of endothelium is the prevention of leak of fluid and cells out of blood vessels. Because of this, we came up with the idea that influenza causes the lung to leak by affecting the endothelium. Scientists don’t know very much about whether the influenza virus can infect endothelium, particularly the endothelium from small blood vessels that supply our vital organs. And if the virus can infect endothelium, it is not known whether this causes blood vessels to leak. Determining whether influenza infects endothelium and causes blood vessels to leak could lead to new treatment strategies and new drugs for severe infections with influenza.
Determining the effect of influenza virus on endothelial cells, which line every blood vessel in the body, is of critical importance to understanding how influenza kills patients. In particular, Dr. Lee’s lab wants to figure out whether influenza virus can infect human endothelium and whether this causes blood vessels to leak. Next, they want to know what happens after endothelial cells are infected that causes them to leak (in other words, the steps that take place inside the cells after influenza infects them), so that we can try to block it. The researchers also want to prove that our experiments using cells imitate what happens during actual infections. To do this, the study will show that in animals, infection with influenza causes blood vessels to leak.
The researchers will prove their theories using a combination of experiments on human cells and animal models of infection with influenza. This combined approach is powerful because it means that what we find from cells can be tested in animal models, which are the necessary first step before trials in human patients. A number of things are unique about the project. First, the theory that influenza infects human endothelium and causes blood vessels to leak is new. Second, the combination of experiments with human endothelium and an animal model of influenza infection is very powerful, making our findings more likely to apply to humans. Third, since endothelial cells from different parts of the body are very different in how they behave, we are testing human endothelium from blood vessels taken from the lung and also from blood vessels in the kidney and in the skin.
Influenza virus is one of the most common infections that threatens Canadians. While most people recover, some develop life-threatening lung damage that causes the lungs to fill with liquid and causes the blood pressure to be dangerously low. This kills as many as 40% of the people who get it. Why this happens is not known, and figuring this out could lead to new drugs or treatment strategies for severe infections with influenza.
Dr. Xing Zhou, McMaster University
Mechanisms of dysregulated immune responses and immunopathology resulting from DAP12 Deficiency in influenza infection
This research deals with lung flu virus infection. Acute lung flu infection is caused by influenza virus and it continues to be an important cause of sickness or even death particularly in children, elderly people and those with chronic disease in North America and elsewhere in the world. Like many other lung viral infectious diseases, often the clinical symptoms and tissue injury in the lung are caused by imbalanced or uncontrolled immune responses that attempt to contain or clear the virus from the lung. Much still remains to be understood as to why this is happening.
The current research project was designed to investigate the mechanisms that help the host to control the immune response that may otherwise damage the lung tissue in the course of acute lung flu virus infection. More specifically, Dr. Zhou’s lab will study the role of a recently identified molecule or protein called DAP12 (DNAX activating protein of 12kDa), that is on the surface of some of our immune cells. Unfortunately little is known about whether and how this molecule may play a role in host defense against lung flu virus infection. In the past half year or so, the researchers have obtained the evidence that this molecule is important in this process as the laboratory animals that do not have this molecule in their immune system become severely ill and some of them die of virus infection within 9 days of time but their illness is not due to enhanced viral infection. In fact, they have found that these animals could control viral infection as well as the wild type animals expressing this molecule. However, the lungs of these animals suffer a much greater extent of inflammation and tissue injury. The researchers have further found that these animals have greater numbers of immune or inflammatory cells in their lungs and elsewhere and if we removed a subset of these immune cells (CD4 T lymphocytes), the animals were better off.
Based on these initial observations, the current project will continue to dissect in more detail the role of DAP12 in regulation of immune responses and lung pathology in the course of lung flu virus infection and its mechanisms. In particular, this study will examine whether and how some of these dysregulated immune cells contribute to harmful and sometimes lethal lung tissue inflammation and injury.
The unique aspect of this project is that it is the first to have identified the critical role of this molecule, DAP12, in determining the level of lung inflammation and tissue injury during flu infection, and that dysregulated CD4 T lymphocytes are the culprit. Therefore, Dr. Zhou’s research will generate new knowledge to help understand why some people die of acute lung flu infection and may eventually lead to the development of novel therapeutic strategies to save more lives.
Dr. Lianne G. Singer, Toronto General Hospital
Determining minimal important differences in health-related quality of life in pulmonary arterial hypertension
To help people with pulmonary arterial hypertension (PAH), we need treatments that improve their health-related quality of life (HRQL). However, we don’t know what sort of changes in quality of life are meaningful or important to people with PAH.
Therefore, the objective of this study is to find out how large a change in quality of life needs to be before it is noticeable to patients with PAH, and what sorts of changes in a patient’s condition bring about noticeable changes in quality of life.
Dr. Singer’s lab will ask patients with PAH to answer questionnaires that are commonly used to measure HRQL. Later, they will answer the same questions again and the researchers will ask them whether their health has changed (whether improved or worsened) between assessments. This will show that the changes in quality of life scores that are associated with noticeable changes in patients’ health. Then, the researchers will study how other changes in patients’ condition (such as new treatments or changes in test results) may bring about these important changes in quality of life.
This unanswered question is very important to patients with PAH. Most prior studies of HRQL in PAH patients have looked at the effect of a single drug on a single measure of HRQL. The researchers are studying many HRQL measures and detailed medical information in a large group of PAH patients who are on a variety of different treatments, which will give us unique information about the factors that affect the HRQL of all PAH patients. Therefore, the result of this research will lead to better care of PAH patients by helping doctors make sure our treatments improve their quality of life in a meaningful way.
Dr. Sherri L. Katz, Children’s Hospital of Eastern Ontario
Co-Existent Obstructive Sleep Apnea and Obesity: Finding NEAT Targets for Intervention
Physical inactivity and childhood obesity are now very common in Canadian children. Obesity causes many health problems in children. Obstructive Sleep Apnea (OSA) is a breathing problem during sleep due to blockage of the upper airway, which occurs with 10 times greater frequency in children with obesity than those of normal weight. It is known to cause sleep disruption and poor sleep quality. Children who have both obesity and OSA are a high-risk group because, despite their young age, their obesity has already led to a significant health problem, which may also impact their lifestyle behaviours (e.g., physical activity and food intake). A better understanding of the lifestyle behaviours of these children would therefore help us design interventions to more effectively help them manage, and hopefully someday overcome their health problems. We are particularly interested in exploring the impact of non-exercise activity thermogenesis (NEAT), which is the energy burned from activities of daily living (e.g., chores, taking the stairs, walking to school), on obesity and OSA. Looking at NEAT levels in children with obesity and/or OSA may help us understand why these children ended up with these problems and more importantly, how we can help them overcome them.
In this study, the researchers investigate how obesity and OSA (both separately and together) affect the following: (1) physical activity and NEAT; (2) appetite and food intake; (3) daytime sleepiness and hyperactivity. Four groups of children will be compared: 1) obesity only, 2) OSA only, 3) obesity + OSA, 4) control (neither condition). Physical activity, NEAT, appetite and food intake as well as daytime sleepiness and hyperactivity will be measured in these 4 groups to see if any of the groups are particularly prone to weight gain because of unhealthy lifestyle behaviours (e.g., eating too much food or not being physically active enough).
This study is unique in that it combines 3 distinct yet complementary areas of expertise: sleep medicine, exercise physiology and clinical obesity management. If obese youth with OSA exhibit particularly low levels of NEAT or physical activity in combination with poor appetite control leading to increased food intake, we should be designing interventions that address these unique and previously disregarded barriers to healthy body weight control in youth. The proposed research project will lead to a better understanding of this population and help in the design of innovative strategies for healthier lifestyle behaviours in these high-risk youth.
Obesity is a rising epidemic in childhood, with health implications in all age groups. OSA, a respiratory complication of obesity, is associated with significant health problems. Early interventions to treat obesity, thereby also treating the cause of OSA, can therefore have significant health impact by improving immediate and long-term health outcomes. Before we can do this, we need to better understand how the presence of obesity together with OSA affects the lifestyle behaviours of youth.
Dr. Bernard Le Foll, Centre for Addiction and Mental Health
Investigating the effects of Varenicline on D2/3 receptor binding in brain of tobacco-smokers
Tobacco dependence is associated with low levels of striatal dopamine D2/3 receptors. This marker of dopaminergic hypo-function is believed to increase relapse vulnerability and it has been suggested that normalizing D2/3 receptors might have therapeutic value. Recently the smoking-cessation drug varenicline has been shown to normalize levels of D2/3 receptors in animal models. It is unknown whether varenicline up-regulates these receptors in human tobacco smokers. The goal of Dr. Foll’s study is to test the hypothesis using in vivo PET and a novel dopamine receptor ligand [11C](+)PHNO that D2/3 receptors are up-regulated after a treatment with varenicline. Pilot data on relationship between changes in D2/3 receptor level and smoking cessation will also be collected.
It is still unclear how varenicline could produce its effects. As addictive properties of nicotine are mediated by the DA system, it appears logical that varenicline could act through the DA system to disrupt addiction. Very few preclinical studies have been conducted to explore this interaction and to our knowledge no studies have been conducted in humans directly exploring the DA system following varenicline exposure.
Therefore, the researchers’ specific hypothesis is that chronic varenicline is acting by up-regulating DRD2/3 in human smokers. This study has multiple aims. First, it seeks to measure the effects of chronic administration of varenicline (standard dose run up protocol to 2 mg per day for 10 days) vs. baseline on [11C]-(+)-PHNO binding in human brain of tobacco smokers (2 hours abstinent) (n=8 subjects). The researchers hypothesize that chronic varenicline administration will increase DA receptors levels ([11C](+)PHNO). Second, it will compare the changes occurring in DRD2/3 enriched areas (caudate, putamen, ventral striatum) and in DRD3 enriched areas (midbrain and globus pallidus). And finally, it will collect pilot data on the relationship between ability to quit smoking and normalization of DRD2/3 by varenicline.
The knowledge gained from this study could lead to understanding on how varenicline is working to treat drug addiction. This will also provide the first insight on how regulation of DRD2/3 could influence therapeutic response, a potential predictor of treatment response that could be used to tailor interventions in the future.
Dr. Laurie A. Zawertailo, Centre for Addiction and Mental Health
Smoking cessation in a residential drug treatment program: A randomized trial of varenicline versus placebo
Smoking prevalence among those with drug and alcohol use disorders can be as high as 90% . Despite this extremely high prevalence, smoking cessation treatment among this population is seldom undertaken, even though many patients express a desire to quit smoking. As well, the negative health effects of smoking among drug and alcohol abusers are substantial as smoking is the leading cause of premature morbidity and mortality among recovered drug users. Therefore, developing smoking cessation treatments for this population has important health ramifications.
There are a few published studies on the feasibility and efficacy of providing concurrent smoking cessation treatment in a residential drug treatment setting with mixed results. Hence, the evidence-base for providing concurrent smoking cessation interventions within residential drug treatment programs is lacking. Furthermore, the efficacy of varenicline, the newest pharmacotherapy for smoking cessation, has not been tested in this population. Therefore, the researchers propose a randomized double-blind placebo-controlled trial to investigate the efficacy of 12-weeks of varenicline treatment combined with intensive psychosocial and behavioural interventions in treating tobacco dependence in a drug and alcohol dependent treatment-seeking population enrolled in a 21-day residential program at the largest mental health and addictions hospital in Canada.
The aim of this study is to assess the efficacy of varenicline compared to placebo in tobacco dependent individuals who are undergoing concurrent treatment for drug or alcohol dependence. As they will be inpatients and under 24 hour medical care for the first 21-days of treatment, this will allow for a comprehensive assessment of the safety of varenicline in this patient population with minimal risk of adverse consequences. The patients will continue their cessation treatment for an additional 9-weeks as outpatients through the Nicotine Dependence Clinic at CAMH. They will also be contacted at 6- months for follow-up.
Dr. Zawartailo’s lab expects that the varenicline-treated group will have significantly higher quit rates at end-of-treatment than the placebo-treated group. Since this will be the first randomized placebo-controlled study to examine the efficacy of varenicline in this subject population, the findings will be novel and important. The potential impact of this study will be significant, especially if it can be demonstrated that this population of smokers is able to quit smoking at the same time they are quitting alcohol without detriment to their recovery from alcohol dependence. Since alcohol consumption and tobacco use are so closely associated (they are more often than not co-administered) it may be therapeutically beneficial to quit both concurrently since smoking can serve as a strong cue or trigger to drink in those who are co-dependent. As well, since tobacco-related illness is the number one cause of death among recovered alcoholics it is imperative that there be provided strong evidence-based treatment options for this population.
All grants are awarded based on ranking by national peer review process conducted by the Canadian Thoracic Society. Budget requests totaling over $2 million. Funding was approved for 15 of the 34 applications to be distributed in descending order of priority, based on their calculated national percentile ranking.
Approved and Recommended for Funding (alphabetically)
|Dr. Dawn M.E. Bowdish, McMaster University||$50,000|
|Macrophage scavenger receptors – novel recognition receptors for|
|Dr. Claudia DosSantos, St. Michael’s Hospital||$50,000|
|ATF3-dependent Molecular Pathways of Injury and Repair in Lung Injury|
|Dr. Manel Jordana, McMaster University||$50,000|
|Impact of flu infections on allergen responsiveness during immune development|
|Dr. Sherri Katz, Children’s Hospital of Eastern Ontario||$49,177|
|Co-Existent Obstructive Sleep Apnea and Obesity: Finding NEAT Targets|
|Dr. Wolfgang Kuebler, St. Michael’s Hospital||$49,652|
|Angiotensin-(1-7) signaling via the Mas receptor constitutes an intrinsic|
|protective pathway and a novel therapeutic strategy in acute lung injury|
|Dr. Mark Larché, McMaster University||$47,925|
|The role of allergen-induced inflammation in the development of chronic airway|
|* Breathe New Life Award recipient 2011-2012:|
|Dr. Warren Lee, University of Toronto||$49,945|
|Influenza infection of human endothelium leads to microvascular leak:|
|cellular and molecular mechanisms|
|**OLA/Pfizer Award Recipient|
|Dr. Bernard LeFoll, Centre for Addiction and Mental Health||$50,000|
|Investigating the effects of Varenicline on D2/3 receptor binding in brain of|
|tobacco-smokers: a PET/[11C](+)PHNO study|
|Dr. Denis O’Donnell, Queen’s University||$49,990|
|Pathophysiological Mechanisms of Dyspnea and Exercise Intolerance in|
|GOLD Stage I COPD: Comparison of Symptomatic and Asymptomatic|
|Dr. Smita Pakhale, The Ottawa Hospital||$37,512|
|A Randomized Controlled Trial of Weight Reduction in Obese Patients with|
|**OLA/Pfizer Award Recipient|
|Dr. Lianne Singer, Toronto General Hospital||$48,282|
|Determining minimal important differences in health-related quality of life in|
|pulmonary arterial hypertension|
|Dr. Ruud Veldhuizen, Lawson Health Research Institute||$48,500|
|Mechanisms of surfactant function and dysfunction|
|Dr. Zhou Xing, McMaster University||$50,000|
|Mechanisms of disregulated immune responses and immunopathology resulting|
|from DAP12 deficiency in|
|Dr. Cory Yamashita, Lawson Health Research Institute||$49,662|
|The Role of Matrix Metalloproteinase-3 in Acute Lung Injury and Multiple|
|Dr. Laurie Zawertailo, Centre for Addiction and Mental Health||$47,600|
|Smoking cessation in a residential drug treatment program: A randomized|
|trial of varenicline versus placebo|
* OLA/OTS Breathe New life Award, total funding includes $33,795 from Top It Up funds
** OLA/Pfizer matching awards in Smoking Cessation and Pulmonary Arterial Hypertension, respectively.