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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 projects funded by the Lung Association during the 2017-2018 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. Sean Gill
Role of TIMPs in pulmonary microvascular endothelial cell activation and dysfunction in lung injury
Amount Awarded: $33,504
Lung injury, and its most severe form, acute respiratory distress syndrome (ARDS), are common and serious lung conditions that affect 10,000 Canadians every year and are fatal in 40% of patients. There are many causes of lung injury, which most commonly occurs following infection, including pneumonia and a widespread (throughout the body) infection called sepsis. Lung injury is characterized by (i) severe lung inflammation and (ii) the leak of fluid and protein from the blood vessels into the airspaces within the lung, leading to fluid-filled lungs and severe respiratory failure. This fluid leak occurs due to injury of the innermost blood vessel lining cells or endothelial cells (EC). There is no current treatment for the severe lung inflammation and fluid leak in patients with lung injury/ARDS.
Our research focuses on understanding how fluid and protein leak from the blood vessels into the airspaces of the lung. A group of enzymes, called metalloproteinases, and their inhibitors, called tissue inhibitors of metalloproteinases (TIMPs), are known to control this leak in other tissues following injury, but this has yet to be shown in the context of lung injury. We will examine how these critical inhibitors, the TIMPs, control the function of blood vessel cells within the lung during both health and injury/infection.
For our work, we use a model of lung injury in mice that results in similar lung inflammation/fluid leak as in patients with ARDS. Once the mice have lung injury, we examine the amount of protein and fluid that leaks from their blood vessels into their lungs. We treat mice with chemical inhibitors (drugs) that block the action of various metalloproteinases to examine how leak is different when these enzymes are inhibited. We also use mice that lack individual TIMPs in blood vessel cells to assess how TIMPs control fluid leak in the presence of injury/infection.
Most studies on EC injury in ARDS have used isolated blood vessels or organs, or have cultured EC from large blood vessels (e.g. umbilical vein). This project is innovative in the following ways:
Our studies will help us understand how fluid and protein leak from blood vessels into the airspaces of the lungs is controlled in ARDS, and may provide information regarding future therapeutic targets. Drugs for these therapeutic targets would potentially decrease death following ARDS, which currently is the main result. Importantly, of the patients that do survive ARDS, many have ongoing difficulties such as shortness of breath and reduced quality of life. Therapeutic targets identified by our work would decrease the damage occurring in the lung as a result of ARDS, which would improve lung function leading to enhanced quality of life for patients that survive ARDS.
Dr. Manoj Lalu
Mesenchymal stem cell exosomes as a novel therapy for acute lung injury
Amount Awarded: $47,188
Life threatening lung injury can occur with serious infections, burns, or trauma. When this occurs in patients it is called ‘acute respiratory distress syndrome’ and they require critical care and mechanical respiration. This is a devastating condition that is a leading cause of death in intensive care units in Canada. Even with modern therapy approximately 30-60% of patients with acute respiratory distress syndrome die. For those who survive this condition there is long term physical, psychological, and emotional dysfunction; only half return to work one year after their severe illness. Clearly, new and innovative treatments are needed for acute respiratory distress syndrome in order to reduce death and improve the recovery of patients who suffer from this condition.
Our previous work has demonstrated that mesenchymal stem cell treatments (“MSCs”, sometimes referred to as adult stem cells) significantly reduce inflammation and decrease death in animal models of acute lung injury. There are still potential problems with using cells in these patients, including “plugging” of vessels in the lungs (which could worsen a patient’s condition), concerns about rejection reactions, and concerns that cells may grow to cause tumours. We believe that ‘exosomes’ released by MSCs may provide the same benefits as the cells while avoiding these potential problems. Exosomes are small vesicles that are released by MSCs and they are filled with molecules that are protective. Here, we propose to investigate whether exosomes from MSCs are protective in acute lung injury.
There are two components of our work. First, we will treat a small animal model of acute lung injury with MSC exosomes. We will measure the effect of exosomes on inflammation in the lung and use state-of-the-art methods to visualize how ‘leaky’ the lungs are. Second, we will investigate the mechanisms that may be responsible for the protective effects of MSC exosomes. We will use a cell culture method in which we induce leakiness (similar to what is seen in lung injury) and then look at the effects of MSC exosomes. We will then block the effects of particular molecules that are known to reside in MSC exosomes. These experiments will pinpoint what parts of MSC exosomes are beneficial.
This will be the first assessment of MSC exosomes on acute lung injury induced ‘leakiness’ both in an animal model and as well as in cell culture experiments. It will provide information required to understand how MSC therapy works. If we demonstrate that MSC exosomes can treat acute lung injury (i.e. only the exosomes are needed, not the cells) then this may lead to “cell-free cell-therapy” – a unique therapy that hasn’t been tried in a clinical trial of patients to date.
Members of our group have successfully conducted first-in-human clinical trials of cell therapy. If MSC exosomes prove to be protective, then we will be uniquely positioned to bring this therapy to the bedside to directly affect Canadians with acute lung injury.
Dr. Anne Ellis
Allergic and Respiratory Outcomes of the Kingston Allergy Birth Cohort (KABC) – The Interplay Between Epigenetics, Outdoor Air Pollution and Environmental Chemicals
Amount Awarded: $44,829
Allergies and asthma are life-long disorders and there is currently no cure available. We do not know why some people develop them and some people do not. A family history of allergies is a risk factor for a child to develop asthma, 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 previously thought. 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 throughout life. We think this “change of clothing” might explain how allergies are passed on to children. These changes are referred to as “epigenetics”. We would like to study how allergies are passed on and if an explanation can be found by looking at epigenetic markers and early life pollution exposures, such as smoking.
We have created ‘The Kingston Allergy Birth Cohort’(KABC), which consists of approximately 400 mother child pairs where the mother donated her umbilical cord blood at birth. More than 150 children, and their mothers, have returned for skin testing to determine if they have allergies at about 2 years of age. In addition, we have survey data on these families regarding respiratory/allergic symptoms and household exposures. Furthermore, we have conducted air pollution sampling at several sites across Kingston, and chemical sampling in 50 homes. We want to use KABC as a model to study development of allergies in children and understand the risk factors such as air pollution that play a role by re-evaluating these children at 5 years of age.
The KABC is a birth cohort that includes urban/rural, smoking/non-smoking, and high/low SES Canadians. Thus, the KABC participants represent diverse exposure profiles that are relevant to the development of allergies and asthma. We have previously shown that maternal smoking during pregnancy, mold, gestatonal age, breastfeeding, siblings and the use of air freshener use in the home modify the risk of parental reports of respiratory symptoms at age 2. Most children in the cohort are now 4 to 5 years of age and this project is requesting funding to allow us to contact all members again, conduct repeat skin testing and surveys to determine respiratory symptoms, access their medical charts and look at the association between their indoor and outdoor air pollution exposure. Furthermore, we will look at the development of allergy, and relate this back to epigenetic markers that may have been present in cord blood to predict these outcomes.
The outcomes of this study will generate new knowledge about the relationships between epigenetics, indoor/outdoor air pollution, and the development of allergies and asthma during childhood. This information will help us to recognize risk factors, and sooner identify children with a higher likelihood of developing asthma and allergies. The earlier we know about these children the quicker we start treatment to reduce, prevent or reverse the development of asthma.
Dr. Chung-Wai Chow
Modulation of the CD200R pathway in a chronic mouse model of allergic airways inflammation
Amount Awarded: $47,189
Asthma is characterized by chronic airway inflammation, hyperresponsiveness (AHR), reversible airflow obstruction and airway remodelling. Despite the availability of effective anti-inflammatory and bronchodilator drugs, the incidence of asthma continues to grow. While the underlying pathogenic mechanisms are not completely understood, multiple genetic and environmental factors, such as exposure to allergens, respiratory viruses and pollutants, are implicated in the pathogenesis of asthma. Chronic inflammation is a prominent feature of the asthmatic airway, and thought to be the underlying mechanisms in AHR and airway remodeling. Development of therapies to modulate the inflammatory response is an ongoing focus of drug therapy in management of asthma.
CD200/CD200R signaling is an anti-inflammatory pathway that has been implicated in a number of chronic inflammatory diseases, including asthma. While CD200 is expressed in hematopoietic and nonhematopoietic cells, CD200R expression is confined to myeloid and lymphoid cells. Activation of CD200R with a recombinant CD200 protein (CD200Fc) was shown to decrease AHR and airway inflammation in a rat model of allergic airways inflammation. Thus, it is the logical to hypothesis that activation of the CD200/CD200R can decrease AHR, airway inflammation and might improve airway remodeling in asthma. We tested this hypothesis in preliminary studies using a newly developed CD200R agonist, a DNA aptamer, in an acute mouse model of allergic airways inflammation. Treatment with the aptamer, given after establishment of the allergic airways phenotype, abrogated AHR and airway inflammation.
The primary objective is to evaluate the CD200/CD200R pathway in an established chronic mouse model of allergic airways inflammation that recapitulates the three salient characteristics of human asthma, namely AHR, airway inflammation and airway remodeling. A secondary objective is to compare intravenous vs inhalational delivery of the aptamer as the latter is preferable (and most commonly used) in treatments of asthma.
We will use a validated 8-week HDM model of chronic airways inflammation for our studies. Following establishment of the ‘asthma’ phenotype, we will treat with the CD200R agonist aptamer, CD200Fc or control aptamer 2 weeks by tail vein injection or intranasal instillation, and then assess:
Application of DNA aptamers, a novel class of drugs with an excellent safety and cost profile, as a therapy for asthma has not been previously studied. Improvement in the management of patients with asthma is one of the key components of the mission of the Lung Association. Developing a viable therapy that targets all three features of asthma, and airway remodeling in particular, has huge potential to decrease the burden of illness of asthma, in terms of improved health and decreased health expenditures.
Dr. Parameswaran Nair
Corticosteroid Insensitivity and Bacterial Bronchitis in Severe Asthma
Amount Awarded: $45,112
Approximately 1 in 8 children and 1 in 10 adult Canadians suffer from asthma – a chronic lung disease that is characterized by difficulty to breathe normally due to lung airway abnormalities. Eosinophils, a white blood cell, are often present in these patients and are believed to be largely responsible for disease symptoms in many of these patients. Treatment with corticosteroids result in a reduction of these cells and improves symptoms. However, some patients still have eosinophils despite being on high-dose steroid therapies, and are called “steroid-insensitive”. For these patients, asthma worsening is frequent, unpredictable and often complicated by recurrent lung infections (bronchitis) needing urgent or emergency department care as well as hospitalization. The precise mechanisms underlying steroidinsensitivity and bacterial bronchitis are not known. Due to this lack of understanding, there are no adequate therapy options to control symptoms in these patients who experience a diminished quality of life.
We believe that a common cellular signaling pathway in these patients involving increased activity of a molecule called Phosphoinositide 3-kinase may be responsible for these patients not responding to corticosteroids and getting frequent chest infections. Therefore, we endeavor to understand this mechanism, towards a goal of identifying a therapeutic strategy for better managing these patients.
We will study patients with severe asthma maintained on corticosteroids and healthy volunteers. Cell and molecular biology techniques established in our lab and elsewhere will be used to determine the signaling events leading to infection and steroid-insensitivity, using both sputum and blood. In patients, we will subsequently determine if steroid-sensitivity can be improved following treatment of lung infection using a personalized antibiotic strategy.
Currently there are no therapy options to effectively manage corticosteroid-dependent severe asthmatics who continue having eosinophils in their airways and experience recurrent chest infections (mostly due to bacteria). In fact, no interventions have been evaluated in this specific asthma population. This study will be the first attempt to thoroughly investigate the viscous cycle of lung infection and steroidinsensitivity in severe asthmatics providing a foundation of knowledge for future clinical studies designed to evaluate novel therapy options.
Canadians with severe asthma experience poor lung health and as a result they utilize substantial health care resources which impose a significant economic burden. Sudden flare-ups in patients whose symptoms are uncontrolled even with high doses of corticosteroids, contribute to 80% of this burden.
Accordingly, to improve clinical outcomes there is an urgent need to better understand the underlying contributors which lead to recurrent infections and steroid-insensitivity. This study proposes mechanistic and clinical studies designed to test a novel hypothesis that can explain the vicious cycle of recurrent infection and steroid-insensitivity experienced by some patients with severe asthma. Validation of this hypothesis will allow us to identify and evaluate therapeutic targets that may improve the management and overall lung health of patients.
Dr. Janet Yamada
A theoretical approach to identifying the barriers and enablers to using an electronic asthma management system in primary care
Amount Awarded: $44,520
Asthma affects 8.1% of Canadians, leads to serious respiratory symptoms, and costs our healthcare system $1.8 billion per year. We developed the Electronic Asthma Management System to enable doctors to easily check their patients’ asthma control level, adjust medications, and prepare an asthma action plan – a written form providing instructions on what to do when symptoms worsen.
Patients answer simple questions about their asthma control on their computer, tablet, or smartphone, and this information is processed and transmitted to their doctor’s computer, along with recommendations for best care. When the patient is in the office, the doctor can click to see the patient’s control, follow recommendations for changes to medications, and easily provide a computer-generated asthma action plan.
Our pilot study of the first version of this tool showed that it does improve healthcare, however less than one third of patients completed the questionnaire and doctors clicked to open recommendations less than one fifth of the time.
This study aims to:
We will conduct focus group and interview sessions with patients and doctors in primary care settings, as well as develop strategies that will improve the current Electronic Asthma Management System.
Not only is our tool unique and innovative, but we will be applying methods from knowledge translation science to detect barriers and enablers to the use of an electronic care tool, which has never previously been done. Our approach might then be repeated to improve other electronic disease management tools.
This study will allow us to improve the Electronic Asthma Management System, which we will then put in place across Canada to improve the quality of care and health of all Canadians with asthma. Also, the knowledge we will gain about the barriers/enablers to use of such electronic tools, and about the methods that can be used to identify and overcome these, will be applicable to similar electronic care tools across respiratory diseases, particularly chronic diseases such as COPD.
Dr. Denis O’Donnell
Mechanisms of Positional Dyspnea in Patients with Advanced COPD
Amount Awarded: $46,518
Patients with advanced chronic obstructive pulmonary disease (COPD) experience shortness of breath during resting quiet breathing. This is often aggravated by changes in body position. For example, many patients experience unpleasant breathing discomfort when lying flat, which can only be relieved by propping themselves with pillows. Positional breathlessness is relevant to the interpretation of sleep studies and indeed, knowledge of pulmonary function changes from the sitting to the lying flat position is necessary to better interpret the results of CT-scans which are conducted with the patient lying flat.
The current proposal will be the first detailed study to examine the precise cause of worsening breathing difficulty in recumbency in severely breathless patients with COPD.
Using sophisticated new technology, we will be able to measure the central drive to breathe from the brain and the activity of the breathing muscles (especially the diaphragm) during changes in position that provoke increased breathing difficulty.
The discovery of the underlying mechanisms of positional breathlessness should provide important new information about the origins of this symptom and will lay the foundation for future studies on sleep-disordered breathing and morning breathing discomfort in severe COPD.
The Lung Association is dedicated to improving the quality of life of Canadians suffering from COPD. This research should increase our understanding of the cause of breathlessness and will, hopefully, allow us to develop more effective treatment strategies to relieve this common distressing symptom in patients with severe COPD.
Dr. Sunita Mulpuru
Impact of a Unique Goal-Directed COPD Care Pathway on Clinical and Patient Reported Outcomes: A Hospital-Based Pilot Feasibility Study
Amount Awarded: $47,189
Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease with no cure that affects over two million Canadians. Patients with advanced COPD suffer with breathlessness, weakness, and repeated flare-up’s of their disease, which often require admission to the hospital or emergency room for treatment. After discharge from hospital, many patients with COPD experience increasing difficulty in coping with daily activities at home.
This inability to cope can lead to hospital readmissions and repeated emergency room visits which are traumatizing for patients and also very costly for the health system. Education for patients with advanced COPD helps them to understand their illness, and has been shown to preserve quality of life while reducing hospitalizations. Despite this, COPD is still a leading cause for hospital admission among chronic diseases in Canada, and patients with COPD continue to experience poor quality of life. Many different health care programs have been designed to address the needs of patients with COPD, but there is not enough information to help us understand which kinds of patients will experience benefit from these programs, how patients benefit in the long term, which components of these programs are most helpful, and how these programs can be expanded to hospitals across Canada.
The objective of this project is to test a unique COPD health care model in a hospital to determine whether we can improve the confidence and ability of patients with COPD to manage their illness, while also improving health care costs and use of resources in the health system. We also aim to find out which parts of this health care model can be used in other hospitals across Canada so that all patients with advanced COPD across Canada may benefit.
We have established an expert team including lung doctors, nurses, respiratory therapists, allied health care workers and health system decision makers to do this work. Our team has worked together for the last one year to create a unique care model which we will use to care for patients admitted to hospital with flare-up’s of COPD. After discharge from hospital, patients will be followed by an outreach program, where they will have access to a nurse, regular follow up, and ongoing education. We will collect information on patients who use this care model to understand how patients with COPD may experience benefit from this program.
Our care model uses a global measure of frailty to set health care goals, guide patient expectations, and direct personalized care to achieve these goals. We are also using a unique patient reported outcome to determine whether this care approach is helpful for patients living with COPD. To our knowledge, this is the first COPD care model to use a clinical frailty scale in this capacity, and first time this will be tested in the ‘real world’ clinical setting.
Our proposed work aims to improve the quality of care for Canadian’s with chronic respiratory disease by testing the effect of a new COPD health care model on patient experience, health confidence, quality of life, and health care costs. This work will provide the foundation for a new approach to care for patients with COPD across Canada.
Dr. Dawn Bowdish, McMaster University
The aging microbiome as a risk factor for developing pneumococcal pneumonia in mid- to late-life
Older adults (50+yrs) are at high risk of developing pneumonia and having pneumonia in mid to late-life can accelerate or worsen the progression of other diseases such as cardiovascular disease, dementia and type 2 diabetes. Therefore preventing pneumonia will provided older adults with more years of healthy independent living.
The bacteria that is the most frequent cause of pneumonia is Streptococcus pneumoniae. Before infection this bacteria must colonize the nasopharynx, which means it binds to the cells that line the sinuses. This is generally asymptomatic but is a pre-requisite to spread to the lung, bloodstream or meninges.
Our study will investigate whether modifications in the upper respiratory tract microbiome can be altered to protect against colonization and spread of S. pneumoniae. Although studies of the microbiome are in their infancy, because the microbiome is modifiable, it is a novel therapeutic target. Currently, we do not have probiotics that are specific for the upper respiratory tract and in order to develop them we need to understand what the “good” bacteria are that are protective against infection. Once we establish this we can determine whether these good bacteria can be harnessed and developed commercially to provide a novel preventative strategy for older adults.
Because vaccination requires an intact immune system, it is not very effective in older adults. The only preventative strategy we have is to vaccinate children, in which it is highly effective to protect older adults by herd immunity. Since pneumonia remains the sixth largest cause of death in Canada, the vast majority in older adults, this is clearly not sufficient. Modifying the microbiome may be a cheap and acceptable adjunct therapy to stop S. pneumoniae colonization and thus infection.
Dr. Jeremy Simpson, University of Guelph
Unexpected progressive non-persistent lung inflammation and diaphragm atrophy following myocardial infraction
Exercise capacity and breathlessness is the chief complaint for patients with cardiac problems which significantly reduce quality of life. Respiratory muscle and lung dysfunction both contribute to reduced exercise capacity and breathlessness. Any improvements in function will be of benefit to patients with heart failure.
These experiments are aimed at identifying the exact cause for the changes we observed in the respiratory system of patients following myocardial infarction. If the current proposal is correct, we will demonstrate lung inflammation and diaphragm dysfunction following myocardial infarction. We will also identify the mechanism, which is important for developing future therapeutics to prevent or treat this disease.
Our aim is to understand the mechanism that causes the changes in the respiratory system that lead to lung inflammation and respiratory muscle dysfunction. We will also test clinically available drugs to prevent the development of lung inflammation and respiratory muscle dysfunction. Our ultimate goal is to understand how these diseases develop following a heart attack so we can find drugs or therapies to stop this progress.
Virtually nothing is known about development of lung inflammation and respiratory muscle dysfunction in the weeks following a heart attack. This work represents the first comprehensive, integrative and multidisciplinary study of the fundamental mechanisms in the development of a heart attack-induced respiratory muscle and lung dysfunction. Additionally, if the current proposal is correct, we will have evidence to support clinically available drugs to use in patients following a heart attack. If we can prevent respiratory muscle and lung dysfunction in patients following heart attack, they will be able to begin rehabilitation earlier and with better gains in recovery.
Dr. Zhou Xing
Mechanisms of viral vaccine-Trained Innate Immunity (TII) against heterologous pneumococcal infection in the lung
Amount Awarded: $47,189
Pneumococcal infection is the leading cause of community-acquired pneumonia and may lead to invasive pneumococcal disease and severe complications in Canada. Host defense in the lung is critical to effective control of pneumococcal infection. However, much still remains to be understood about the factors that may influence such anti-pneumococcal host defense.
The main objective of our project is to understand whether prior history of viral-based respiratory mucosal vaccination may influence host defense against subsequent pneumococcal infection in the lung, and if so, what are the immune mechanisms.
We will use our recently established mouse models to address this question. We will vaccinate, via the respiratory route, the animals with a viral-vectored tuberculosis vaccine and then expose these animals to pneumococci. We will examine pneumococcal disease outcomes and immune responses, and compare these with the responses seen in animals that were not previously vaccinated.
Our project sets out to investigate a clinically relevant new question that has never been addressed before. With the current human Flumist vaccine and an increasing number of new vaccines being developed for respiratory mucosal route of vaccination, it is of importance to understand whether and how it may affect host defense in the lung against subsequent exposure to pneumococcal pathogens.
As pneumococcal infection represents an important health issue in Canada, the new knowledge from our project will help develop improved preventive and therapeutic strategies against pneumococcal disease. It will also provide the evidence to support introducing the consideration of both the targetspecific and off-target effects of current and future respiratory mucosal vaccination strategies into human vaccination policy development.
Dr. Matthew Miller
Unravelling the role of antibody-mediated Fc-dependent effector functions in mucosal immunity against influenza virus
Amount Awarded: $47,189
Influenza virus infections remain one of the top 5 leading causes of death worldwide. In Canada, seasonal influenza virus infections are estimated to cause over 12 000 hospitalization and over 3,500 deaths each year. Severe illness and death occur most commonly in individuals with heart and lung conditions, including asthma and chronic obstructive pulmonary disease. Vaccination remains the most effective way to prevent influenza. While neutralizing antibody levels in the blood correlate well with protection, the factors protect against influenza virus infection in the lung remain unclear.
Our goal is to determine how neutrophils, the most abundant white blood cell type and the first to respond to infection, interact with the IgA antibodies that are found in the lung to help protect against influenza virus infection.
We will use primary human neutrophils and antibodies to study how neutrophils respond to IgA-coated influenza virus. We will then test the neutrophil responses induced by the antibodies of children who received the “flu shot”, and compare that to those who received the “FluMist” vaccine. We will then determine whether the strength of these responses correlate with protection against infection.
Although neutralizing antibodies in the blood are known to correlate with protection against influenza virus, very little is known about the factors that protect against influenza in the lung, especially in response to “FluMist®” vaccination. Our study focuses on the interaction between the most abundant type of white blood cell (neutrophils) and the most common type of antibody in the lung (neutrophils).
Incredibly, the interaction between these factors has never been examined in the context of influenza virus infection. Our preliminary results suggest that this interaction causes neutrophils to undergo a process called “NETosis” – a function which has never before been reported for IgA-coated virus. Importantly, using archived clinical trial samples, we have the ability to determine whether this activity correlates with protection in children who received the FluMist vaccine.
Influenza virus infections cause millions of hospitalizations, and hundreds of thousands of deaths globally each year. In Canada, publicly-funded vaccination programs have been adopted to avert infection, however thousands continue to die every year during flu season. There has been serious controversy over the past several years regarding the effectiveness of the “FluMist” vaccine. Part of this controversy is routed in the fact that no strong immunological correlates of protection have been established for the “FluMist”. Our study will define a new mechanism through which the antibodies generated by “FluMist” might contribute to protection against infection. Determining the extent to which this response correlates with protection will provide critical information that will inform studies of influenza virus vaccine efficacy, and lead to the development of more effective vaccines.
Dr. Stephen Lapinsky
Mechanical ventilation in obstetric patients
Amount Awarded: $46,321
Critical illness in pregnancy is uncommon but devastating. Severe lung conditions are a common cause of critical illness and death in pregnancy, and these womenmay require support from a breathing machine (mechanical ventilation). In Ontario, about 40 pregnant women each year require mechanical ventilation.
Doctors who look after patients needing mechanical ventilation are guided by several studies over the past 20 years, which have identified how to manage critically ill patients without causing further damage to the lungs or other organs. Unfortunately, most of these studies have excluded pregnant women, and so there is little information to guide ventilator management during pregnancy. Because ventilation during pregnancy is an uncommon occurrence, few doctors or centers get sufficient experience or sufficient patients to study these issues. Our group has previously performed a study of ventilated pregnant woman collected from 4 ICS’s around the world, which identified several questions that still need to be answered, eg. The ideal volume of air to provide per breathe and whether delivery of the baby will improve the mother.
The objectives of the project are to develop a Core Outcome Set (ie. minimal outcomes to be reported in future studies of pregnant woman with severe lung disease receiving mechanical ventilation) and set up an online Registry to collect date about pregnant women who are managed with mechanical ventilation. By collecting detailed information from a large number of ICUs around the world, we hope to generate sufficient data to answer the following questions:
The Core Outcome Set will be developed by reviewing current studies and getting agreement with an international group of doctors, nurses and patients/family members. For the Registry, we will set up a secure, simple system for doctors at ICUs around the world to upload patient data, when they have a pregnant woman requiring mechanical ventilation in their ICU. We have initiated collaboration with expert sites, identifying 8 ICUs in 6 countries who admit a large volume of critically ill pregnant women. With recruitment of additional sites, we anticipate obtaining data on about 100 women per year.
Critical illness in pregnancy is a relatively rare but important condition that has not been adequately studied. We have created a unique international group of doctors and researchers who are interested in collaborating on projects to improve this knowledge. This will be the first Core Outcome Set developed for studies of critically ill pregnant women and the only international registry of critically ill pregnant women.
This project aims to generate new knowledge to improve breathing and optimize mechanical ventilation in pregnant women with very severe lung disease. This knowledge will be used to decrease mortality and morbidity to affected mothers and their offspring.
Dr. Jonathan Draper
Modeling pulmonary fibrosis using patient-derived pluripotent stem cells
Amount Awarded: $46,684
Idiopathic pulmonary fibrosis is a disease that damages the lung in a way that prevents that patient from breathing normally and currently has no cure. This disease usually kills patients within 3 years of diagnosis. How idiopathic pulmonary fibrosis (IPF) begins and then destroys normal structure of the lung is not understood, mostly because the early stages of the disease are not easily watched in the lungs of patients, and also because the disease is difficult to mimic when lung cells are grown in a dish in a laboratory.
Our objectives are two-fold: First, to identify new genes that can provide susceptibility to a patient for developing pulmonary fibrosis, and second to create a system for studying idiopathic pulmonary fibrosis in a laboratory dish, providing a simple and easily accessible way to watch the start and continuation of the disease.
We are using pluripotent stem cells, which are cells that can be converted or differentiated into any cell type in the body by treating the stem cells step-by-step with different culture media. In addition, adult cells in the body like skin can be converted back to stem cells and then converted to any cell type. We have developed a recipe for converting stem cells into 3D lung tissue containing lung cell types. We have obtained blood samples from patients with and inherited form of IPF, called familial pulmonary fibrosis (FPF), and “reprogrammed” them into pluripotent stem cells. We will now differentiate these FPF pluripotent stem cells into 3D lung tissue. By doing this we will create a “disease in a dish” model of IPF, because the converted cells will be patient-specific and will carry the genetic mutations associated with the hereditary form of pulmonary fibrosis.
We have access to a previously unstudied family cohort who have a genetic basis for their susceptibility to PF, which has allowed us to identify new genes that have not yet been associated with this disease. We have obtained samples from the FPF family members and generated pluripotent stem cells to model PF in a laboratory dish. Here we will use these cells to create a system that gives us the ability to understand aspects of PF outside the body that may not be possible to study in the patients themselves. It may help us determine the causes of IPF and how genetic mutations make patients susceptible to fibrosis-causing agents. Since pluripotent stem cells can be expanded indefinitely in culture and maintained in an unspecialized state, this provides an infinite population of patient-specific cells for use in disease modelling. In addition, generating lung tissue in a dish from patient-derived pluripotent stem cells provides an alternative to collecting lung biopsies.
A system that captures the characteristics of idiopathic pulmonary fibrosis in a laboratory dish would greatly help in understanding and preventing the start of this deadly disease. Such a system will later allow the finding and testing of new drugs and treatments that will stop the disease from killing patients. Importantly, the system that we have created could also be used to understand other forms of lung disease, including cystic fibrosis, emphysema or bronchitis.
Dr. Martin Stampfli
Impact of cigarette smoke on dendritic cell phenotype and function in the upper respiratory tract mucosa
Amount Awarded: $49,850
Smoking-related diseases are a major cause of suffering and death in Canada and worldwide. It is well known that smoking causes heart and lung diseases, as well as cancer. Cigarette smoking is also an important risk factor for respiratory infections, a significant cause of illness and mortality. While we need to continue to promote smoking cessation and prevention programs, we also need a better understanding of how smoking predisposes to respiratory infections, given the highly addictive nature of smoking and the burden these infections place on our health care system and society.
The nose is as a key entry point for harmful viruses and bacteria into the lungs. The objective of our project is to investigate whether cigarette smoking suppresses immune responses against viruses and bacteria in the nose, predisposing to infection of the lungs. In the proposed research, we will specifically investigate whether smoking impairs the nose’s ability to recognize bacterial components and elicit protective immune responses.
We will pursue our research in experimental models of cigarette smoke exposure. We will assess immune function using purified agents from harmful bacteria, as well as state of the art flow cytometric analyses, a tool that allows us to study individual cells from the nose and other associated tissues.
There is increasing recognition that cigarette smoking weakens the immune system. Surprisingly, how cigarette smoking impacts immune responses in the nose has been overlooked and is currently not understood. Hence, the project addresses an important knowledge gap. The long-term goal of our research is to develop novel drugs to restore immune function in the nose. This experimental approach is innovative, as we aim to prevent infections rather than dealing with the consequences of infection.
The Ontario Lung Association is dedicated to improving respiratory health through medical research. The impact of cigarette smoking on immune responses in the nose is still poorly understood. The proposed studies will further our understanding of how smoking predisposes to respiratory infections and provide novel insight into how smoking-related diseases develop.
Dr. Cory Yamashita
Optimization of a Host-Defense Peptide Fortified Surfactant for Clinical Use
Amount Awarded: $45,492
Lung infections resulting from bacteria represent one of the leading causes of death worldwide. Furthermore, the emergence of a greater number of lung infections resulting from bacteria that are resistant to antibiotics has become problematic and are associated with poor outcomes such as death. The traditional approach of using intravenous or oral antibiotics may also be ineffective in getting the antibiotic to regions of the lung where the infection is most abundant.
Host defense peptides (HDPs) are proteins that have been shown to be effective in killing antibioticresistant bacteria and may represent a potential solution to this problem. Our research team has also demonstrated that these HDPs could be administered directly to the lung through the airways with the use of a lipid/ protein mixture known as surfactant which can facilitate the transport of HDPs to the site of infection. Some of these studies however have also shown that when HDPs and surfactant are combined together, the antibiotic (killing) properties of the HDPs are reduced and that specific properties of the surfactant may be in part responsible for this. If, however, this surfactant compound could be manipulated in order maintain the excellent bacterial killing properties of these HDPs, this would provide a significant step forward in the development of this innovative therapy that could be further tested for clinical use.
In order to further develop this therapy, optimization of the surfactant component of this compound will be necessary in order to limit inhibitory effects on HDP killing function. The overall objective of this project will be to develop an understanding of how surfactant interferes with HDP antimicrobial function in order to generate a new surfactant with minimized inhibitory effects on the HDPs. Thus, the intent of this research project will be to develop a compound with both excellent killing and spreading properties when combined together.
To test our hypothesis we will use different preparations of both a natural and synthetic surfactant compound and test the effectiveness in killing antibiotic-resistant bacteria under laboratory conditions. Furthermore, we will assess several different HDPs to determine ideal HDP and surfactant combinations.
Overall, the results of these studies will have important implications for the development of an innovative therapy for the treatment of bacterial lung infections. In particular, a diverse range of Canadians are affected by antibiotic-resistant lung infection including those with cystic fibrosis, chronic obstructive pulmonary disease and severe community-acquired pneumonia, where new treatment options are urgently needed.
Dr. Kyle Cowan
Targeted Delivery of Elastase Inhibitors to Reverse Congenital Diaphragmatic Hernia Associated Pulmonary Vascular Disease
Amount Awarded: $47,189
Congenital diaphragmatic hernia (CDH) occurs when the diaphragm fails to completely close while the fetus is developing in the mother’s uterus. The resultant opening in the diaphragm allows abdominal organs such as intestines, stomach, and liver to move into the chest cavity, which prevents the lungs of the fetus from fully developing. As a result, close to half of infants born with CDH die due to pulmonary hypertension (PH).
PH is a type of high blood pressure that affects blood vessels called arteries in the lungs, as well as the right side of the heart. PH is a very serious pulmonary vascular disease (PVD) as its progression can cause heart failure and death. As existing treatments for controlling PH are most often unsuccessful in CDH infants, a novel therapy is greatly needed for these patients.
We have shown using a rat model of CDH that a type of matrix enzyme, named elastase, is activated in CDH pulmonary arteries. Our data so far indicate that elastase levels are also increased in the lung arteries of babies that died of CDH. My previous studies have demonstrated that elastase contributes to PH development and that blocking its activity could completely treat PH in adult rats and increase their survival.
We now have identified that the elastase activated in CDH rats can be blocked by two native inhibitors that are found in our bodies, namely elafin and alpha-1 antitrypsin (A1). Interestingly, transplanted progenitor cells, which are generic cells that can differentiate into a specific cell type, have been shown to specifically home to blood vessels of the lungs and deliver therapeutic molecules of interest in adults.
Our objective is now to use these cells to target and deliver elafin and A1 to the diseased lung vasculature of rat fetuses affected with CDH and determine whether it can improve the PH and survival of these pups. c) How will you undertake your work? We will use a rat model of CDH that is known to mimic the clinical condition found in patients with CDH and associated PH.
Progenitor cells engineered to secrete elafin or A1 will then be delivered to pregnant rats using an administration approach that has shown successful transplantation into the lungs of their fetuses. We will next determine whether these cells modified to secrete elafin or A1 can reach the lung vasculature of rat fetuses and successfully deliver active elafin and A1 to this site. Finally, we will assess whether this approach can improve the PVD and survival of CDH rat pups.
Our work has the potential to identify a viable approach to deliver potential therapeutic molecules to the lungs and pulmonary arteries of CDH fetuses/newborns. Furthermore, data from this project will reveal whether elafin and/or A1 may constitute a novel treatment approach to treat the PVD associated with CDH.
The project described here will identify a viable strategy to block elastase activity in fetal CDH lungs as well as to develop expertise in progenitor cell approaches to deliver therapeutic molecules to fetuses and newborns with CDH. Establishing a viable cell therapy approach will also set the stage for the delivery of other potential molecular treatments for CDH or other lung disorders as they become identified in the future. This proposed study is thus a critical step towards determining whether blocking elastase activity can trigger regression of the PH associated with CDH and improve survival, and advancing our goal of applying our findings as a therapy for CDH patients.
The mission of The Lung Association is to lead nationwide and international lung health initiatives, prevent lung disease, help people manage lung disease and promote lung health. In order to improve lung health, this proposed project targets the lack of effective treatment for PH in patients with CDH. This proposed project, which evaluates the feasibility of a novel therapeutic approach, is part of our research program whose goal is to develop an innovative strategy to successfully treat PH in infants with CDH to increase their chance of survival and long-term outcome.
In addition to CDH babies, this new treatment could also benefit infants, children, and adult patients affected with PH resulting from other causes, preventing heart failure, and death, and thus help in the management of a broad spectrum of lung diseases.
Dr. Gaspard Montandon
Targeting regulators of G-protein signaling to prevent opioid-induced respiratory depression
Amount Awarded: $47,081
Opioid medications are widely used as pain killers but have the serious side-effects of respiratory depression. When opioids are abused, respiratory depression can be deadly. In the United States alone, there are about 20,000 deaths per year due to overdoses by opioids such as morphine, heroin, fentanyl, and oxycodone (Centers for Disease Control and Prevention). Unfortunately, there is currently no medication to prevent and reduce the life-threatening side-effect of respiratory depression by opioids, while preserving the beneficial analgesic properties of opioid medications.
Opioid medications depress breathing by acting on special receptors in brain regions regulating breathing. However, how these receptors in the brain inhibit breathing is unknown. Our research aims to identify new ways to develop therapies that prevent respiratory depression by opioids before opioid overdose happens.
Using basic research, our aim is to identify specific proteins in the brain that are keys to opioid inhibition of brain cell function important to breathing and may be targeted to prevent respiratory depression by opioid medications.
There is currently no commercially available medication to prevent respiratory depression by opioids mainly because our understanding of the mechanisms underlying inhibition by opioids is limited. Our basic research is the first to investigate the underlying mechanisms responsible of respiratory depression by opioids. If successful, our research will lead to new approaches to develop therapeutic strategies to prevent the side-effect of opioids while preserving their analgesic properties.
Pain is a major problem in patients with acute and chronic diseases such as cancer or after surgical interventions. The most common and widely-use medications to reduce moderate to severe pain are opioid analgesics, but the risk of respiratory depression considerably limits their use.
When opioids are abused, they can lead to severe respiratory depression and lethal overdose unless treated. The mortality and health burden associated with opioids are therefore considerable in Canada and our research aims to identify new treatments to reduce opioid-induced respiratory depression while preserving the positive effects of opioid pain killers.
Dr. Chris Verschoor
Correlates of lung function in older Canadians: a comprehensive, multi-disciplinary approach
Amount Awarded: $47,189
Lung health and function are arguably two of the most important components of health and wellness as we age. For older adults even a minor loss in breathing ability can have a substantial impact on their risk of disease and hospitalization, being able to live at home, and overall lifespan. As a nation the issue of lung health and function in older adults is slowly becoming urgent. During the remainder of the 21st century, we will experience an unprecedented shift in the proportion of adults greater than 60 years old, nearly doubling by the year 2060, and because of this, health-care spending related to lung health will skyrocket. It is clear that we need to better understand the causes of lung function decline in Canadians, especially in our older population.
Our study aims to provide a thorough investigation of the lifestyle, health and disease and psychosocial related factors that influence lung function in older Canadian adults. These factors include specific areas that are common to all of us and are generally modifiable or preventable; for example: physical activity and nutrition, depression, socioeconomic status, acute and chronic diseases, alcohol consumption and participation in social activities. We are going to look at Canadians that do not have any obvious cause of lung health loss (eg. non-smokers, those without asthma or COPD), and will specifically examine the effect of these factors in men and women, and within discrete life stages (ie. young-old/middle-aged, mid-old/seniors, old-old/elderly).
To complete these goals we are going to use information recorded on participants taking part in the Canadian Longitudinal Study on Aging (CLSA). This will include up to 30,000 individuals between 45 and 85 years old from across the country that have provided detailed questionnaire data as well as lung function testing by spirometry.
The most important aspects of this work is that unlike most other studies:
Identifying the factors related to lung function in older adults and understanding the contribution they make will greatly benefit not only the lung health of Canadians as they age, but also their ability the maintain overall health and well-being into their golden years.
Dr. Edmond Young
SELA-Chip: Developing a microfluidic airway organ-on-a-chip system for advanced studies in respiratory health
Amount Awarded: $37,751
Chronic lung diseases such as asthma and bronchitis are a major health problem in Canada and around the world. In Canada alone, chronic lung diseases will affect over 5½ million people by 2020. New drugs and therapies are urgently needed to help those with lung disease, but discovering new drugs requires deeper understanding of how lung airways work, and requires high quality tools in the lab for testing the effectiveness of new drugs on human lung tissue samples. Lung airway tissue is complex, and consists of different types of biological cells that communicate with each other. Two important cell types are the airway epithelial cells that form the inner lining of the airway, and the smooth muscle cells that provide strength to the airway structure. Although researchers have made progress in our understanding of cell communication, much of what we know about communication between epithelial cells and smooth muscle cells is being debated because of important differences between tissue models we use in the lab (such as lab mice) and real airway tissue in humans. Therefore, new experimental tools must be invented so that lab results can better represent effects of real human tissues.
The main objective of this project is to develop a brand new experimental model of human lung airway tissue in a microchip device, consisting of properly organized and functioning airway epithelial cells and smooth muscle cells that together accurately mimic the airway tissue of the human lung. The new airway-on-a-chip tissue model will exhibit the same physical features and perform many of the same functions as real human airway tissue, including mucus production, beating cilia on the epithelial cells that help move the mucus, alignment of smooth muscle cells, and the presence of airflow to simulate inhaling and exhaling of air.
The Young lab has expertise in micro-engineering techniques and development of microscale technologies for biomedical applications, and has already begun work designing and testing the airway-on-a-chip concept. Early results show excellent potential for achieving an accurate living model of human lung tissue made of an individual’s very own cells. We will use our techniques to engineer the airway-on-a-chip device with microscale precision, load the device with living human airway cells, allow the cells to attach to biomaterial surfaces that simulate lung tissue materials, and then introduce air into the device to simulate breathing. Once our new airway-on-a-chip is built, we will test how cells in the device respond to different conditions, and compare these responses to how cells behave in other traditional culture systems.
This project aims to develop a brand-new airway tissue model that will, for the first time, incorporate primary human airway epithelial and smooth muscle cells together on opposite sides of a suspended gel layer, all within a microscale device that can accommodate airflow for simulating breathing. While some current microscale devices have attempted to model lung tissue, none of them use a suspended gel layer, and none of them use smooth muscle cells in their coculture. These two features make the proposed system unique in the field.
The proposed research will result in a new airway-on-a-chip tissue model that will enable scientists to perform important experiments for studying cell communication between airway epithelial and smooth muscle cells. These experiments will advance our understanding of how chronic lung diseases develop, accelerate the discovery of new drugs and therapies, and improve treatment and management for people afflicted with lung disease.