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Dr. Azedeh Yadollahi, Toronto Rehab Institute
Assessment of the Adverse Effects of Rostral Fluid Shift on the Pathophysiology of Asthma
In patients with asthma, resistance to airflow in the lung airways is higher than in the healthy subjects. Resistance to airflow and other asthma symptoms such as coughing and wheezing are more severe during sleep. Deep inspirations are one of the most efficient ways to reduce airway resistance in healthy subjects; however for unknown reasons, their efficiency is much lower in asthma patients.
The objectives of this study are:
The proposed program will explore a plausible mechanism that could influence asthma treatment, explain why asthma symptoms worsen during sleep, why older patients are at higher risks due to the worsening of asthma symptoms and why deep inspiration are less effective in opening obstructed airways. If it can show that electrical stimulation would reduce the lower airway resistance, we can develop non-pharmacological interventions to improve asthma.
Dr. Parameswaran Nair, Firestone Institute Respiratory Health St. Joseph’s Healthcare
Investigating local autoimmunity in severe eosinophilic asthma
Eosinophils, a type of white blood cell, are a characteristic feature in many airway disorders which obstructs natural breathing and disrupt one’s quality of life e.g. asthma. Most difficult-to-control eosinophil associated lung disorders are treated with a drug called prednisone (glucocorticosteroid) to control the underlying inflammation and prevent symptoms and attacks. Prednisone has severe side effects and undesired by most patients. Even then, for reasons not yet known, the clinical symptoms of some patients remain uncontrolled, causing frequent ‘flare-ups’ that require immediate medical attention and hospitalization. In many diseases, our own body produces antibodies directed against our own tissues and organs. This phenomenon of autoantibody production is called autoimmunity and this is not described in asthma.
Eosinophils produce a protein called eosinophil peroxidase which can cause damage to surrounding lung tissue. In other diseases where certain peroxidase levels are increased such as thyroid peroxidase (autoimmune thyroiditis) and myeloperoxidase (Granulomatosis with polyangitis), autoantibodies are detected against the peroxidase itself, that lead to disease.
In this study, we propose that a similar phenomenon may be present in some patients with severe asthma where a high level of eosinophil peroxidase is detected in the airway. Hopefully, in doing these studies we will not only investigate an unknown inflammatory component in the diseased airways, but also identify a sub-set of patients who may require increased anti-inflammatory drugs.
This study proposes a novel hypothesis that can explain such phenomenon in severe diseased airways and allow us to identify and formulate a better therapeutic plan for managing such patients.
Dr. Teresa To, The Hospital for Sick Children
The Impact of Air Pollution on the Progression of Asthma to Chronic Obstructive Pulmonary Disease (ACOS) in Women
Individuals with both asthma and chronic obstructive pulmonary disease (COPD), called asthma and COPD overlap syndrome (ACOS), have more rapid decline in lung function, more frequent respiratory exacerbations, and worse quality of life than those with asthma or COPD alone.
Exposure to air pollution is a known risk factor shared with asthma and COPD, however, its role in the natural history of ACOS is not well understood. In women, the prevalence of COPD has continued to rise substantially in the last decade. Furthermore, research has shown that women make up a larger proportion of the non-smoker COPD population, suggesting that women may be more vulnerable to other environmental risk factors associated with COPD (such as air pollution) that are not related to smoking.
This will be one of the largest population-based cohort studies with a long observation period (over 30 years of follow-up) that examines the impact of air pollution on the onset of ACOS in women.
The results of this study will add evidence of the relationship between air pollution and disease progression (from asthma to COPD) in women. Our study findings will inform the design of prevention initiatives that aim to decrease the risk of continued loss of lung function that leads to COPD in women.
Dr. Denis O’Donnell, Queens University
Detection of clinically important respiratory impairment in adult smokers: which test is most sensitive?
Chronic obstructive pulmonary disease (COPD), in most cases, is related to tobacco smoking but it is well established that only a minority of smokers (~25%) meet breathing test criteria for COPD diagnosis. However, many smokers who don’t meet these criteria develop persistent (and often troublesome) respiratory symptoms such as cough, sputum production and shortness of breath with activity. In particular, population studies have shown that the presence of shortness of breath in “at risk” smokers increases the risk for reduced survival and poor quality of life.
We reasoned, based on a number of recent studies in patients with mild COPD that extensive damage to the smallest airways and blood vessels exist in the lungs of many smokers who do not have a diagnosis of COPD by breathing tests. We have begun to collect evidence to support the notion that this impairment of lung function – not captured by conventional breathing tests – can reduce the individual’s ability to engage in physical activity.
In the current application we propose to characterize, for the first time, the nature and extent of the lung function impairment during the stress of exercise in smokers with a history of persisting shortness of breath who are at risk for developing COPD.
This work should identify distinctive patterns of lung damage in smokers which will explain their breathing difficulty during physical activity. The study may help identify new tests for the early detection of lung function impairment in smokers and hopefully set the stage for targeted exploration.
Dr. Carl Richards, McMaster University
Oncostatin M Receptor signaling and cancer growth in lungs
Cancer in our lungs is very difficult for doctors to treat and more than eight out of 10 people die within five years if they get lung cancer. These cancers progress very quickly in lungs but how and why they do this needs research to help discover new methods or medicines to help these patients. We will complete research that will test our question whether a certain hormone-like protein molecule called “Oncostatin M” can regulate cancer growth in lungs. We believe that this hormone-protein, which is involved in inflammatory lung diseases like asthma, also plays a new role in assisting cancers to grow. We believe it does so by utilizing the body’s own cells to nurture the tumour, and that smoking cigarettes increases the levels of Oncostatin M in lungs. We will test whether interfering with Oncostatin M will decrease lung tumours.
If the results of our experiments support our predictions, this may significantly impact potential approaches to controlling growth of lung cancers. This may also provide more information on how other kinds of cancers that metastasize to lungs may be controlled. These basic science studies may also provide a foundation for other lines of research in exploring new methods to treat this important lung disease.
Dr. Gonzalo Alvarez, Ottawa Hospital Research
Application of whole genome sequencing to uncover transmission dynamics and quantify transmission of smear negative TB disease
Many aboriginal communities in the north of Canada have a heavy burden of tuberculosis (TB) disease that is much higher than the rest of the country. The number of people who get sick with active TB in Nunavut has risen over the past 10 years so that it is 60 times higher than the rest of Canada. A person who las a large amount of TB bacteria in the sputnum from their lungs has what is called smear positive TB disease. If there is a small amount of bacteria in the sputnum, it is called smear negative TB disease.
Research done in places with warm weather shows that smear negative TB disease is not very contagious. We think that it is possible that in northern Aboriginal communities smear negative TB disease is more contagious than this research shows. These northern communities are different because:
This project will look at how TB disease moved between people in two communities in Iqaluit and Cape Dorset, Nunavut, between the years of 2009 to 2015 to figure out the proportion of people with smear negative disease who pass the disease on to someone else.
This research would use a new test to see if movement of TB between people is different in the colder communities in the Canadian north. It would also help health-care professionals come up with new ways of preventing people from being infected with TB in Aboriginal communities across Canada.
Dr. Sunita Mulpuru, The Ottawa Hospital
Impact of Respiratory Viruses in Canadian COPD Patients: A Multi-Centre Cohort Study
Patients with chronic obstructive pulmonary disease (COPD) can experience flare-up’s which result in increased cough, weakness, and shortness of breath. These flare-up’s often require the patient to come to hospital for treatment. Up to 60 per cent of flare-up’s can be caused by infection with a respiratory virus, such as the flu. Research studies have shown that COPD patients who are infected with a respiratory virus have more severe symptoms, take longer to recover and are prone to even more flare-up’s in the future.
However, these previous studies were very small and did not examine how respiratory viruses might affect other important outcomes, such as the chance of death, time spent in hospital, impact on weakness, and ability to function after discharge from hospital. The objective of this project is to determine how respiratory viruses impact Canadian COPD patients who are admitted to hospital. We want to understand the chance of death, length of hospitalization, and degree of weakness in COPD patients with and without a respiratory virus.
This project is the largest study to evaluate the effect of respiratory viruses on important outcomes in patients with COPD, and has never been done in Canada. The project will create a partnership between lung doctors, researchers, laboratory experts and experts in public health, which will produce a strong foundation for further research in this area. We will use advanced techniques to detect several respiratory viruses in COPD patients admitted to hospital, and collaborate with over 40 hospitals across Canada. Having a better understanding of how respiratory viruses affect COPD patients is very important so that new treatments can be used.
Dr. Michael Surette, McMaster University
Host-pathogen strain specificity as determinant in complicated pneumonia and pleural empyema
It is surprising that for almost half of patients with pneumonia a cause (bacteria or virus) cannot be identified. When treatment fails or because of other complications, pneumonia can progress to more serious infections of the chest cavity. We are interested in understanding these complications and to identify the organisms responsible. We are particularly interested in one group of bacteria that cause almost half of these complicated infections but are not well studied in lung infections (Streptococcus Milleri/Anginosus Group).
Our goal is to understand what bacteria cause these infections and how the immune system of the host responds. By understanding this, we will be able to identify patients at risk and to guide more effective treatments.
Our goal is to improve the treatment of these infections by better understanding the bacteria that cause them and how the patient immune system is responding. This should lead to more effective ways to treat these patients (e.g. getting the right antibiotic by knowing what bacteria is responsible). The results will also be applicable to other chronic airway diseases such as COPD and asthma which can be complicated by infections but most often no pathogen is identified.
Dr. Sean Gill, University of Western Ontario
Pulmonary microvascular endothelial cell activation during lung injury is regulated by TIMP3
Lung injury leads to acute respiratory distress syndrome (ARDS), which affects many Canadians every year and is often fatal. This lung injury, which is associated with severe inflammation, can result from a direct insult to the lung, such as a lung infection, or from an indirect insult to the lung, commonly occurring following a widespread (throughout the body) infection called sepsis. One of the serious complications from ARDS is the leak of fluid and protein from the blood vessels into the airspaces within the lung, leading to fluid-filled lungs and difficulty breathing. There is no current treatment for ARDS patients and as a result, death occurs in almost 40 per cent of patients.
Our research focuses on understanding how fluid and protein leak from the blood vessels into the airspaces of the lung. Inflammatory cells, through interaction with the cells of the blood vessels, are often associated with this leak. A group of enzymes, called metalloproteinases, and their inhibitors, called tissue inhibitors of metalloproteinases (TIMPs), are known to control inflammation in the lung following injury. As well, this enzyme/inhibitor family are thought to control leak in other tissues following injury, but this has yet to be shown in the context of lung injury. We will examine how the metalloproteinases and TIMPs control the function of blood vessel cells within the lung during both health and infection.
Our studies will help us understand how inflammation as well as fluid and protein leak from blood vessels into the airspaces of the lungs is controlled following ARDS and may provide information regarding possible therapeutic targets. 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 of patients following injury.
Dr. Tereza Martinu, Toronto General Hospital
IL-17A in chronic lung allograft rejection
Over 4,000 lung transplants are performed worldwide each year in patients with end-stage lung disease who have failed all medical therapy. Unfortunately, only 50 per cent of the patients survive beyond five years, mainly due to the development of chronic rejection. Chronic rejection causes scarring of the transplanted lung, which is ultimately fatal in most patients. This scarring is not well understood and no effective therapies exist.
The objective of this project is to better understand the mechanisms of lung scarring that occurs during chronic lung rejection. The signalling protein IL-17A has been found to be elevated in the lungs of patients with chronic lung rejection. Blocking this IL-17A protein in animal models of lung transplantation appears to reduce chronic rejection. However, we do not understand which cells are important in making this protein and which cells respond to its signal. Understanding the IL-17A communication pathway is important to further characterize the chronic rejection process and also to develop targeted therapies for this disease. The specific aim of this project is to determine whether the donor lung cells or the recipient immune cells are important in making or responding to IL-17A.
We will achieve the aim by using a state-of-the art mouse model of single lung transplantation. We will study their development of chronic lung scarring and determine, which cells must have IL-17A or its receptor in order for scarring to develop.
Understanding how chronic rejection develops and injures the lung is key to develop better treatment.
Dr. Michelle Kho, McMaster University
CYCLE Pilot: A Pilot Randomized Study of Early Cycle Ergometry versus Routine Physiotherapy in Mechanically Ventilated Patients
Survivors of critical illness are typically very weak and disabled. Over half of these patients have severe leg weakness impairing their quality of life for as long as five years after ICU discharge. In-bed cycling uses special equipment that attaches to a patient’s hospital bed, allowing them gentle leg exercise while in the ICU.
The main goal of this research program is to see if patients who need a breathing machine recover faster if they receive early in-bed cycling than those who do not. To-date, no researchers have studied the use of early in-bed cycling in the ICU and how it affects issues important to patients (e.g., walking, quality of life). We know that if patients receive in-bed cycling after they have been in the ICU for two weeks or more, they will walk farther when they leave the hospital than those who did not receive cycling. This study will give us important information about whether three different ICUs can provide the same in-bed cycling very early in a patient’s ICU stay.
This research, starting gentle exercise very early with patients requiring breathing machines, will help them keep or improve their muscle strength while their lungs heal.
Dr. Niall Ferguson, Toronto General Hospital
Diaphragm Activity and Function during Mechanical Ventilation: the MYOTRAUMA Study
Mechanical ventilation is a life-saving intervention for people whose lungs are failing. Most patients recover and are able to breathe on their own after a short time on the ventilator. However, some patients require support from the mechanical ventilator for many days or weeks. One important reason for this delayed recovery is weakness of the muscles used for breathing, especially the diaphragm. Because a strong diaphragm is necessary for breathing without ventilator support, diaphragm muscle weakness keeps patients dependent on the ventilator. During this prolonged weaning from the ventilator in the ICU patients may experience complications including delirium, infections, and death that might not occur if they could breathe on their own sooner. Just as any muscle that is rested for too long will get weak, research in animals suggests that mechanical ventilation may rest the diaphragm too much and make it weak. These animal studies also suggest that providing ventilator breaths that are out-of-sync with the diaphragm contractions will also weaken this important breathing muscle.
We want to know whether these findings are true in patients. If they are true, then while mechanical ventilation is life-saving in the short term, it may actually prevent patients from recovering from respiratory failure.
This study will be the first to directly examine whether too much diaphragm rest and out-of-sync breathing can cause diaphragm weakness in patients on ventilators in the intensive care unit. The results of our study will be used to design a new ventilation strategy to prevent diaphragm weakness and reduce prolonged dependence on ventilators with its known complications. Ultimately, this research, if successful, will help patients to recover from lung failure more quickly and improve their long-term recovery.
Dr. Reshma Amin, The Hospital for Sick Children
Health Service Utilization and Costs in Children Receiving Long-term Home Mechanical Ventilation in Ontario
The number of children that use a mechanical ventilator (a machine that supports breathing) at home (HMV) is increasing around the world. This is because of better medical care, better ventilators to use at home and also the knowledge that it is better for the entire family if the child using HMV lives at home instead of in the hospital. In Canada, we don’t know how many children use HMV. We also don’t know how many children in Ontario or across the country start to use HMV every year, what kinds of health-care services they use and what their costs are. This information is important when planning for the future to make sure we can continue to support these children living at home with their families where they belong.
Our main research objective is to identify the types of health-care services that are used by HMV children in Ontario and how much they cost. We also want to find out if there are differences based on the type of breathing support used by the child and what factors may result in more service use and higher costs. Other research objectives are to determine how many children in Ontario have started using HMV over a ten year period. We also want to find out if health-care service use and costs change when a child starts to use HMV.
This will be the first study of health-care service use and costs using health data for the population of HMV children in Ontario. We will describe the health-care services used and the associated costs for HMV children in Ontario over the past ten years. This will help the Ministry of Health and Long-Term Care make changes to the health-care system to improve care to these children and their families.
Dr. Kjetil Ask, McMaster University
IRE1 mediated XBP1 splicing is required for Fibroblast Differentiation and Macrophage Polarization
Lung fibrosis is a disease, which is often fatal 2. It affects about 15,000 Canadians with approximately 6,000 new diagnoses made each year. In lung fibrosis, scar tissue accumulates in the area in between the alveoli. These alveoli are responsible for the exchange of oxygen for carbon dioxide and depend on the elastic properties of this area to expand and contract. When scars accumulate the elastic properties are lost and breathing becomes incredibly difficult. It is thought that the accumulation of scar tissue is due to an out of control wound healing mechanism. This mechanism is due in part to macrophages which in fibrosis send out excessive wound healing signals. These wound healing signals cause scar producing cells to become overly active and lay down scar tissue.
Our project aims to understand a process called endoplasmic reticulum (ER) expansion. This process involves enlarging the size of this organelle to accommodate increased production of various molecules. If we can interrupt the molecular mechanisms driving this expansion we could prevent unnecessary secretion of wound healing signalling molecules by macrophages and scar tissue secretion from fibroblasts.
There is little evidence in the biomedical literature regarding the process of endoplasmic reticulum expansion in the context of the macrophage or the fibroblast and by further understanding the specific mechanisms involved new therapeutic targets could be found. Our research will be helping the biomedical community to further understand scarring in the lung.
Though our projects are doing this with a focus on pulmonary fibrosis the overall scarring involved is very likely to have many similarities with the airway remodelling found in other diseases such as asthma and COPD. If we can further understand the role of ER expansion in our models of scarring we can potentially find various novel molecular mechanisms involved in scar formation. If we can target these therapeutically we could find new treatments for scarring in the lung.
Dr. Sarah Wootton, University of Guelph
Nuclease-based gene targeting for correction of alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin (AAT) deficiency is a genetic disorder commonly associated with adult onset lung diseases, including emphysema, chronic obstructive pulmonary disease (COPD) and airway inflammation and affects an estimated 190 million people worldwide. The AAT protein is normally made in the liver, and in addition to lung related disease, a subset of individuals with severe AAT deficiency are at risk to develop serious liver complications. Treatment options for AAT deficiency include inhaled bronchodilators and steroids, pulmonary rehabilitation and in the more severe cases, lung transplant. These treatments however only address the symptoms of AAT deficiency, but do not address the underlying cause (i.e. defective AAT protein). Protein replacement therapy is also available to people with AAT deficiency associated lung disease and consists of weekly intravenous infusions of normal AAT protein purified from healthy blood donors. While this approach may be effective for lung-related AAT disease, protein replacement therapy does not address liver related disease.
Additionally, the requirement for weekly infusions for life, along with the high cost of this therapy makes it an unsustainable option. A promising alternative treatment for AAT deficiency is gene therapy. The idea behind gene therapy is to provide an individual who has defective copies of the AAT gene, with a functional, good copy of the gene. Recently great strides have been made in gene therapy, however none of the current approaches can permanently deliver a good copy of the AAT gene into the human genome in a controlled manner.
Our proposal is to compare two newly developed cutting-edge genome editing technologies (TALEN and CRISPR), to insert a functional copy of the AAT gene, permanently, into a safe location within the human genome. Our approach will not only deliver a good copy of the gene, but will also suppress the bad copies. By delivering a good copy of the gene we can cure the lung related disease, and by suppressing the bad copies we can cure the liver related disease.
By developing new gene therapy approaches using TALEN and CRISPR technologies we can potentially cure a wide variety of genetic diseases such as AAT deficiency, cystic fibrosis and haemophilia. Results from these experiments will not only inform us as to which of the gene targeting platforms has the greatest ability to promote sustained AAT expression but will also assess whether a dual function gene therapy vector could be useful for the treatment of Z-AAT induced liver disease.