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HOPE IS IN THE AIR. For all our big breathing breakthroughs, there is so much more that still needs to be done. Diagnostic tests and treatments can still be improved. The secrets of our immune systems need to be unlocked. And we have yet to fully harness the awesome power of gene therapy. With your support The Lung Association continues to fund some of the smartest minds around as they work tirelessly to transform people’s lives. Breathtaking stuff.

Research Reports

2018 Research Report

Current Projects (2018-2019)

Asthma →
Cystic Fibrosis
Infectious Disease

Lung Transplant

Neonatal Lung Disease


Pulmonary Fibrosis

Pulmonary Hypertension

Sleep Disordered Breathing



Dr. Dhenuka Radhakrishnan
Derivation of clinical score to predict risk of future emergency department visits and hospitalizations among children with Asthma
Amount Awarded: $50,000

Asthma is one of the most common chronic diseases in childhood and is a leading cause of emergency department (ED) visits and hospitalizations. Despite improvements in available treatments, ED visit and hospitilization rates for asthma remain high. Currently, children who leave the ED following an asthma exacerbation do not always receive comprehensive asthma education or get started on asthma controller medications, even though these strategies are known to prevent repeat asthma visits. This may be due to physician discomfort in prescribing these treatments or lack of asthma educators. However, these treatments are likely only needed for children who are at high risk for repeat ED visits or asthma hospitalizations. There are currently no guidelines to direct clinicians how to practically identify these high-risk children before discharge from the ED.

Our aim is to derive an ED-based clinical risk score to identify children at highest risk for a repeat asthma ED visit or future hospitalization within 12 months following an initial ED visit for asthma. We will analyze data that was collected as part of a previous study that included all children with an asthma exacerbation who came to the ED at one of five specialized paediatric hospitals. Information on characteristics of children who participated in this previous study will be linked with provincial health administrative date in Ontario and Quebec to provide information on health care outcomes one year after their initial ED visit, and specifically whether the children were hospitalized or had repeat ED visits for asthma. This information will be used to develop a clinical score to identify high-risk asthma patients.

This study fills the current knowledge gap, and has the potential to significantly change the way we target and manage children at the time of discharge from the ED in order to reduce future repeat acute health care visits. We have identified a creative way to perform this study quickly and cost-effectively as it will utilize patient-level data that has already been accurately collected at multiple Canadian centres in a previously funded study. Since we will be linking this previously collected data to high quality provincial health administrative data to identify the study outcomes, our study findings will be relevant to all children across Ontario and Quebec and can even be applied across Canada.

It is estimated that 25% of children who visit the ED for an asthma exacerbation will have a (preventable) repeat asthma ED visit or hospitalization within one year. We propose that development of a clinical score that can be practically used in the ED setting to identify these high-risk children would allow efficient targeting of proven preventative interventions to the right patients. Having a method to identify this target group would also help in the design of future research studies aiming to test the effectiveness of new strategies to prevent repeat asthma acute health care visits. In short, developing a clinical risk score to identify high-risk children is the first step in our aim to ultimately prevent up to 20% of childhood ED visits, as well as the breathing problems, anxiety and life/work disruption experienced by this group of children and their families.

Dr. Roma Sehmi
Role of TL1A/Death Domain Receptor 3 (DR3) axis in the activation of ILC2 in Asthma
Amount Awarded: $50,000

Asthma is a chronic disease of the airways that affects more that 3 million people in Canada and it’s incidence is increasing. 1 in 3 individuals in Ontario will receive a physician diagnosis of asthma during their lifetime. Despite the development of anti-asthma drugs, many asthmatics continue to have worsening breathlessness as they age. Investigating biological processes that cause the symptoms of asthma may reveal new drug targets to treat uncontrolled breathlessness that worsens over time in asthmatics.

After asthmatics inhale particles to which they are allergic, their lungs become inflamed and their asthma worsens. During this process, recruitment to the lung of mature cells such as eosinophils and basophils and their precursor cells occurs. These cells, when activated release cell-derived products which damage the lung tissue and symptoms of asthma develop such as airway narrowing and mucus over production. Identifying factors/cells that promote and expand eosinophil numbers in the airways may provide a valuable target for treatment of asthma. In the last decade, a novel group of cells termed “Group 2 innate lymphoid cells (ILC2s)” have been discovered as a major tissue source of factors that promote eosinophil growth, recruitment and activation in the lung tissue. In asthma our group has found that ILC2 producing pro-eosinophilic cytokines are increased in the airways in patients with uncontrolled symptoms despite high doses of steroids. As well, we reported that ILC2 provide the initiation signal for allergic asthmatic responses. Little however is known about all the factors that recruit and activate ILC2 in asthmatic airways. This project will investigate the role of a factor known as tumor necrosis like factor 1A (TL1A) and changes in its receptor (death receptor 3; DR3) expression on ILC2 in the airways in asthmatic responses. We will test the effect of corticosteroids, the gold-standard for treatment of asthma, on DR3 expression on ILC2.

Using an allergen exposure model that is well established in our laboratory, we will study subjects who are induced to have an asthmatic response as a result of a controlled inhalation of a compound to which they are allergic. By taking sputum samples coughed up from the airways, level of expression of DR3 on ILC2 cells and amount of TL1A in sputum will be assessed. The time points chosen to sample sputum before and after allergen challenge are well defined as time points at which maximum increases in airway eosinophil numbers occur. We will investigate expression levels of DR3 on ILC2 from sputum (a) before and after an allergic asthmatic response, (b) compare these changes with cell types that produce eosinophil growth factors such as T cells, and (c) by isolating ILC2s from blood (as these are too rare to isolate from sputum), we will investigate what effect this receptor has on ILC function and the ability of corticosteroids to interfere with this effect. Effects on ILC2s will be compared to T cells, as the latter are known to be steroid sensitive cells.

Animal studies show that ILC2 are an important local source of growth factors that promote expansion of cells that cause many of the symptoms of asthma. Understanding the role of ILC2 in human eosinophilic asthma is a new and important field. By comparing activation of ILC2s and T cells, and investigating the effect of known drugs on modulating this activation, this study will provide unique drug targets that may be beneficial in asthmatics who continue to have uncontrolled symptoms despite being treated with high doses of corticosteroids.

Increased numbers of eosinophils is a prominent feature of the asthmatic lung and studies have shown that this feature increases as the symptoms of this disease worsen. By understanding the role of cells that promote the persistence of eosinophils in the lung, we aim to better treat this condition. 

Dr. Azadeh Yadollahi
Investigating whether Bronchodilator Medications can Prevent Effects of Rostral Fluid Shift on Airway Narrowing in Asthma
Amount Awarded: $50,000

Asthma affects 8% of Canadians and its health related costs are $600M annually. Nocturnal exacerbation of asthma is a clinically important phenotype of asthma and is common in two-thirds of asthma patients. Nocturnal asthma is associated with increased use of asthma medication, more severe asthma symptoms, and greater asthma related morbidity and mortality. The recumbent posture and sleep increase lower airways narrowing and nocturnal asthma.

Emergency visits due to asthma exacerbation, calls to physicians, and death due to asthma are more common during the night. Despite optimum treatments, nocturnal symptoms remain a major concern and mechanisms accounting for nocturnal asthma remain unclear. We propose that lying down during sleep causes shifts of body fluids from the legs to the chest and neck, and this rostral fluid shift exacerbates narrowing of small airways in lungs in patients with asthma. Fluid accumulation in the chest can increase bronchial blood volume, narrow the airway lumen, and thus contributes to asthma severity and fatality.

Our objective is to demonstrate that in patients with nocturnal asthma, bronchodilating medications do not prevent the airway narrowing due to fluid shift. Asthmatics with and without nocturnal asthma will be randomized to receive placebo or bronchodilator. Then, they will lie supine for 30 minutes and their legs will be squeezed for 25 minutes (from 5 mins to 30 mins) to increase fluid shift out of the legs and simulate the amount of fluid shift that occurs at night. A week later they will be crossed over to the other study arm. In both study arms, we will measure fluid volumes in the leg and chest, and airway resistance at 0 min and 30 min. We expect that in patients with nocturnal asthma, even with bronchodilator treatment, increased fluid shift into the chest will increase airway resistance.

Post-mortem analysis of the lungs show that airway walls are thicker in asthmatics who died from fatal asthma attacks than from other causes. Acute changes in airway wall thickness can occur from local edema due to vascular leakage in the airway wall. One of the principal mechanisms by which increased excess airway fluid can increase airway resistance is through entering the airway adventitia, swelling the airway wall and decreasing the airway lumen. As this mechanism is independent of contraction of the airway smooth muscle, it would not be expected that it would be prevented by bronchodilating medication. Demonstrating this is of clinical relevance, as long acting bronchodilating medication in combination with inhaled steroids is the principle component of current guidelines for the prevention of nocturnal asthma. With this proposal, we intend to demonstrate that bronchodilating treatment does not address all mechanisms of nocturnal airway narrowing in asthma.

This research addresses physiological mechanisms that apply to an important clinical problem. Understanding the mechanisms of lower airway narrowing due to fluid shift will facilitate development of new treatments for nocturnal asthma by reducing fluid shifts and their pernicious effects. These treatments can be as simple and practical as use of compression stockings during the day, exercise, diuretics, or head elevation during sleep. If supported by the data, this practicality, together with their translational impact, would comprise the greatest strengths of this research.


Dr. Jeremy Hirota
Inhibiting ABCC4 to potentiate β2-agonist and glucocorticoid responses in COPD
Amount Awarded: $49,750

Chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis are responsible for over $5 billion of direct health care costs each year in Canada, impacting over 3 million Canadians of varying demographics. Presently there are no cures for these chronic respiratory diseases with treatment strategies instead targeting symptoms to control inflammation in the lung and how easily air can enter and leave the lungs. Unfortunately, for a subset of individuals with COPD, the best-approved medications fail to work optimally. Exploring new ways to improve how the best-approved medications work in these COPD patients may provide new treatment strategies for controlling lung inflammation, easing the process of breathing, and provide health care savings in Canada.

We will study how a molecule called ATP Binding Cassette Transporter C4 (ABCC4) works in the lung to stop inflammation and prevent the damaging effects of cigarette smoke, using cells from humans and an animal model of COPD. We will use two distinct approaches for our proposed research:

  • We will perform experiments on airway epithelial cells, the first line of defence in the lung, removed from healthy subjects and those with COPD to examine how the best-approved medications work in these subjects and how drugs targeting ABCC4 could improve their activity.
  • We will perform experiments using a mouse model of chronic cigarette smoke exposure that mimics human COPD. For this experiment, we will use genetically modified mice that are deficient in the ABCC4 molecule. Relative to genetically normal mice, we anticipate that genetically modified mice that lack ABCC4 will have a better response to the best-approved drugs.

To our knowledge, we are the first in the world to explore how the best-approved drugs could be improved by also blocking ABCC4. Our published results in human cells already demonstrate that this can work, but this is only from healthy individuals, which may vary from individuals with COPD and a history of smoking. We need to confirm that this happens in cells from individuals with COPD and in a mouse model of COPD. The combination of our experiments using clinically relevant human cell samples and genetically modified mice gives our research group a competitive edge that is unique internationally. We also have a provisional patent on novel ABCC4 inhibitor compounds that we will test in our proposed experiments.

COPD management is a significant cost and burden on the health care system in Canada and throughout the world. To manage COPD, it is recommended to use relievers and controllers that allow the air to come in and out of the lungs more easily and to reduce lung inflammation, respectively. The best-approved drugs do not work in all COPD patients, leaving many prone to difficulty in breathing and frequent hospitalizations. Improving how the best-approved drugs work in these difficult to treat COPD patients will improve their lives and those of their caregivers. Our study is the first to explore how a molecule called ABCC4 may be crucial to improving how the best-approved drugs work in COPD patients. If the results of our proposed studies are promising, we can pursue the development of our novel drugs that inhibit ABCC4 as potential new therapies to help the thousands of Canadians living with COPD.

Dr. Nicholas Vozoris
The potential impact of synthetic oral cannabinoid use on respiratory outcomes among older adults with COPD
Amount Awarded: $29,625

Chronic obstructive pulmonary disease (COPD) is a common, long-term, lung disorder caused by being exposed to cigarette smoke or biomass fuels. COPD affects about 4-10% of Canadians and occurs more often among older adults. COPD is the leading cause of coming to hospital in Canada among those with chronic sicknesses and it poses a big financial strain on our health care system. COPD can often cause more than just lung symptoms, including such things as chronic pain and poor sleep. Cannabinoids are a class of prescription drugs with pain-reducing and sleep-promoting abilities. Cannabinoids are chemically similar to pot, except that they come in pill form and are swallowed. By potentially reducing pain, poor sleep and difficult-to-control shortness of breath, cannabinoid drugs may help prevent people with COPD from suddenly getting unwell in terms of their lungs. However, there are several ways that cannabinoids might also negatively affect the lung health of people with COPD. We do not have studies on how cannabinoid drugs affect the lung health of people with COPD. The extent and the ways with which cannabinoids drugs are presently used among people with COPD are also unknown.

The purposes of this research are:

  • To describe the extent and ways in which cannabinoid drugs are presently being used among older adults with COPD versus older adults without COPD.
  • Among older adults with COPD, to evaluate what potential impact cannabinoid drugs have on lung health, specifically, on acute lung illness and death.

This study will involve analysis of data contained in multiple, Ontario government, health databases. The health databases contain information on the sociodemographics, health, prescription drug use, and health care system use of Ontarians. Individuals diagnosed with COPD and users of cannabinoid drugs will be identified from these databases. Negative lung-related events will be examined among new and non-users of cannabinoids, including COPD or pneumonia-related doctor visits, emergency room visits, hospitalizations, intensive care unit admissions and death.

This study is unique because it will be based on an analysis of a very large and population representative sample of about 150,000 older Ontarians with COPD. There is no information presently available on the scope and pattern of cannabinoid drug use among older adults with COPD, nor on the potential impact of cannabinoid drug use on lung health in this population.

Our research will help patients and health care professionals better understand what potential impact cannabinoid drugs have on lung health in COPD and this is a topic that we presently know little about. If cannabinoids are found to have good effects, our research may lead to these drugs being used more often and helping people with COPD, especially those persons who are suffering from chronic pain, poor sleep or difficult-to-control shortness of breath. If cannabinoids are found to have negative effects, doctors will know to be more careful about prescribing cannabinoids, and as a result, older adults with COPD may be protected from possible bad medication effects.


Dr. Subash Sad
Mechanisms of host cell necrosis during pulmonary exacerbation in cystic fibrosis

Amount Awarded: $50,000

Cystic fibrosis (CF) is one of the most common genetic diseases with an incidence of around 1 in 2,500. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which impairs transport of chloride ions in cells. This results in dehydration of the airway mucus, progressive fibrosis and alteration in lung physiology. As a result, lungs of CF patients become highly susceptible to opportunistic bacterial infections. Up to 80% of CF patients become infected with P. aeruginosa, which accelerates the lung disease progression in children. Recurrent episodes of pulmonary (lung) symptoms termed “exacerbations” are very common in CF patients, which are associated with increased bacterial colonization, airway inflammation and decreased lung function. Aggressive antibiotic therapy during pulmonary exacerbations controls the disease, which suggests that pulmonary exacerbations are linked to bacterial infection. However, it is not clear how the chronic lung infection and the specific environmental triggers cause the switch to exacerbation.

Infection with virulent pathogens results in tissue necrosis, which can become fatal if not controlled early. Recently two major inflammatory cell death platforms termed inflammasomes and necrosomes have been discovered that are induced by the bacterial virulence factors, which synergistically cause rupture of infected cells, and massive induction of inflammation and tissue necrosis. We aim to decipher whether these inflammatory hubs promote pulmonary exacerbations of CF patients.

Our first aim is to isolate P. aeruginosa from the sputum of CF patients during the stable and exacerbation phases, and infect monocytes, neutrophils and epithelial cells with these bacteria. Monocytes and neutrophils will be directly purified from peripheral blood using labeled magnetic beads and primary epithelial cells will be obtained commercially. Activation of inflammasome/ necrosome platforms in infected cells will be evaluated by cell biological analysis (cell imaging, colorimetric and western blotting). Our second aim is to test the impact of P. aeruginosa on cells with a mutation in the CFTR gene.

Inflammasome and necrosome signaling of host cells is induced by the most virulent hub of the bacterium, the bacterial type III secretion system (T3SS). The bacterial isolates that we have obtained from the sputum of CF patients have all been sequenced. We will perform bio-informatic analysis of T3SS of  P. aeruginosa isolated from CF patients to identify specific changes that occur during exacerbations.

The first innovation is the delineation of inflammatory cell death mechanisms during pulmonary exacerbations that lead to wide spread tissue necrosis. A second innovation is the use of clinical samples of P. aeruginosa that are all sequenced, and are isolated during the stable and exacerbation phase of CF. The third innovation is the evaluation of the diversity of all bacterial isolates in the sputum samples of CF patients for their impact on cell/tissue necrosis.

We study natural infections using bacteria that are isolated from CF patients. We evaluate the mechanisms that induce tissue necrosis in the lungs. We also evaluate the impact of host mutation on induction of cell necrosis. We anticipate that our research outcomes will shift the field towards systemic analysis of inflammatory cell death platforms in CF pathogenesis, which will lead to the discovery of new therapeutic approaches.


Dr. Jane Batt
Genomic Epidemiology of M. Abscessus in Pulmonary Disease
Amount Awarded: $44,450

Mycobacterium abscessus, a member of the non-tuberculous mycobacteria (NTM), is an emerging respiratory pathogen in people with chronic lung disease. In the Cystic Fibrosis (CF) patient, M. abscessus infection is associated with worsening lung function and poor outcomes following lung transplantation. Treatment of the organism requires months of therapy with multiple poorly-tolerated antibiotics. Since M. abscessus is multi-drug resistant, cure is often impossible. Given its increasing occurrence and its negative impact on the health of people with lung disease, prevention of infection is vital. Infection with NTM was thought to occur exclusively from the environment. This dogma has been recently challenged for M. abscessus. Using a novel technique called Whole Genome Sequencing (WGS), which reads the unique genetic code for each bacteria, researchers in the UK in 2016 presented evidence that was highly suggestive of M. abscessus person-to-person spread among CF patients. However, they did not provide epidemiologic support to confirm transmission, nor did they did determine whether this potential transmission was unique to CF, or also occurring in patients with other lung diseases.

Currently, there are no special infection control measures implemented in Canadian hospitals for the non-CF patient with M. abscessus. In contrast, CF clinics in Toronto recently undertook special infection control precautions and now only assess M. abscessus patients in negative pressure rooms. These rooms are an expensive, limited hospital resource that are essential to treat patients with dangerous respiratory infections that spread person-to-person and can infect an entire population, such as tuberculosis. Our lack of understanding of how M. abscessus is spread is limiting our ability to provide sound, safe, and cost-effective care.

We aim to determine whether there is evidence supporting possible person-to-person transmission of M. abscessus occurring in Ontario hospitals with current infection control practices in place. We will perform WGS of M. abscessus isolates from patients treated in 3 Toronto hospital specialized CF clinics and NTM clinics. Sharing of highly genetically similar organisms between patients will support the possibility of person- to- person spread; genetically distinct organisms in different individuals will not.

We will be the first group to assess for potential strain sharing of M. abscessus in Canadian CF centres, and the first worldwide to assess for potential strain sharing in patients with non-CF related lung disease. Our project provides immediate value to Canadians. It will inform current infection control (IC) measures, as we will provide precise, scientific evidence hospitals can use to adjust their IC practices in CF and non-CF lung disease patients. If we demonstrate strain sharing this project will provide critical pilot data for future study to determine how the organisms are spread (ie droplet vs aerosol) and how M. abscessus subspecies impact lung disease progression and treatment outcomes.

Dr. Sarah Wootton
In vivo Adeno-Associated Virus (AAV) Surfactant Protein B gene delivery system for lung regeneration
Amount Awarded: $49,998.50

The lung is made of pipes (conducting airways) that deliver oxygen to millions of air sacs (alveoli) where oxygen is taken up by the blood and distributed to the rest of the body. These air sacs are coated with surfactant. Surfactant keeps the air sacs wide open to insure exchange of oxygen. Surfactant is made out of a mixture of proteins and lipids and produced by lung cells (called type 2 alveolar epithelial cells, AEC2). Amongst these surfactant proteins, surfactant protein B (SP-B) decreases lung surface tension to keep the alveoli wide open. Unfortunately, there is a rare, but lethal genetic disease in which SP-B is abnormal. The gene that produces SP-B protein is called SFTPB. Babies born with mutations in SFTPB have trouble breathing at birth because the alveoli are crumpled and cannot open. These babies usually die. Currently, there is no therapy except lung transplantation, which is not always possible.

Our goal is to deliver the healthy SFTPB gene into the lung by using gene therapy in animal models of SP-B deficiency. We will take advantage of a unique recombinant adeno-associated virus (AAV) that we have engineered to be stable and highly efficient in targeting the lung. This is a safe, replication defective viral vector that can target AEC2s. We will deliver the healthy SFTPB gene into the lungs of a mouse model of SP-B deficiency. We will test if this genetic tool can improve the breathing problems of these mice. We are combining the expertise of two Ontario scientists that have decades of training in our respective fields. I have trained my entire career on viruses and how to engineer them for therapeutic purposes. Dr. Bernard Thébaud is a clinical neonatologist caring for critically ill babies and a research scientist that has made it his mission to develop cures for lung diseases in babies.

Delivering the SFTPB gene with our AAV vector into an animal model of SP-B deficiency has never been attempted. If successful, we will have provided proof of concept that this technology can lead to a cure for a lethal genetic lung disease. It could also benefit other genetic diseases for which there is no treatment today. The mission statement 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.” The proposed research tackles an important lung problem: to provide a treatment for patients with genetic lung diseases who either die at birth due to a genetic defect or contribute to 10% of pulmonary fibrosis patients. The proposed research will test a new approach to correct the genetic defect using a new gene therapy approach as a life-saving therapy. Our study will provide proof of concept for the feasibility and efficacy of such an approach. Our study has the potential to save the lives of babies world-wide. Importantly, the results of our study will be relevant to other life-threatening genetic lung diseases that currently lack treatments.


Dr. Chung-Wai Chow
Impulse Oscillometry for Early Detection of Small Airway Obstruction
Amount Awarded: $50,000

Many airway diseases such as bronchiolitis obliterans, asthma and chronic obstructive lung disease (COPD) begin in the small airways, an area known as the ‘silent zone’ as changes in small airway function are not detected by available diagnostic tests. Conventional pulmonary function tests (cPFT), with spirometry and FEV1 (forced expiratory volume in 1 sec), is the gold standard metric of lung function. However, FEV1 is largely sensitive to central airway obstruction 1,2 and cannot detect changes in the small airways until 75% of all the small airways are occluded 3,4. In the context of lung transplant (LTx) where graft function is critically impacted by small airway function, spirometry is used to monitor development of acute rejection (AR) and chronic lung allograft dysfunction (CLAD) although it is known that both begin in the small airways. AR occurs in 30-50% of patients within the first year post-LTx5,6, and is the single highest risk for development of CLAD. CLAD develops in 50% of all LTx recipients by year 5, and is the major impediment to long-term survival post-LTx6.

Unsurprisingly, spirometry has only a 60% sensitivity for detecting clinically significant AR7. Bronchoscopy with transbronchial biopsies (TBBx) is also routinely conducted post-LTx. However, TBBx usually only contains a few small airways and is associated with complications such as bleeding and pneumothorax8 . Further, it has a discovery rate of AR of only 47-57%9-11. Forced oscillometry (FO) is a simple PFT that directly assesses small airways. It detects lung function changes earlier than cPFT in COPD12 and found to be a better metric of asthma control in children13,14. While spirometry is a forced manoeuver1,2, FO is conducted during normal breathing and requires minimal patient cooperation, an advantage early post-LTx, where chest discomfort is common.

We posit that FO detects airflow obstruction with a greater sensitivity than cPFT, FEV1 and TBBx following LTx. Therefore, lung function monitoring with FO will lead to earlier diagnosis of AR and CLAD, with the potential for earlier intervention and better clinical outcomes. The overall goal of the research programme is to compare the sensitivity of FO with cPFT in detection of CLAD post-LTx.

The goal of the current proposal is to conduct a study to compare FO with spirometry and FEV1 in detecting AR during the first 18 months post-LTx, a period when the incidence of AR is high. We will build on a pilot study already underway that is enrolling 80 new double LTx recipients for FO testing, with follow-up of only 3 months. The current study will prolong follow-up to 18 months and increase the sample size to 100. All LTx patients are evaluated with weekly outpatient cPFT at University Health Network (UHN) for the initial 3 months post-LTx. Thereafter, cPFT are conducted at UHN during assessment visits at 3, 6, 9, 12, 18 and 24 month post-LTx. We will conduct FO prior to each routine post-LTx cPFT at UHN; this study design allows for comparison of paired FO and spirometric measurements for every time-point for all patients. We will also collect clinical data that affect lung function; these include human leukocyte antigen matching, TBBx findings and infections. The statistical analysis will be conducted in collaboration with the Biostatistics Research Unit at UHN (https://thebru.ca/). Correlations between repeated measures will be conducted according to the methods of Bland and Altman15,16 to assess the significance of correlations between oscillometric and spirometric parameters, as well as these parameters with clinical and histological diagnosis of AR.

This is the first study to directly compare FO with spirometry post-LTx, a clinical scenario where development of small airway obstruction is a predictable event. As such, it is an almost perfect clinical model to compare the sensitivity of FO with FEV1 in detecting small airway obstruction. Our research is expected to offer robust data to support the use of FO for monitoring of small airway disease for multiple etiologies, and thus lead to earlier diagnosis of AR post-LTx as well as more common diseases such as COPD and asthma, and in this way, improve lung health in Canada.


Dr. Ruud Veldhuizen
Post-natal effects of intra-uterine growth retardation on the lung and its response to sepsis
Amount Awarded: $50,000

Our lab studies a condition call Acute Respiratory Distress Syndrome which has no known cure and a mortality rate of 30-40%. Research studies have investigated this disease however, most of those studies utilize healthy adult male animals despite the fact that ARDS occurs in males and females at different ages and often in people susceptible to the disease. Our goal is to use animal models of the disease that better reflect the human population, specifically, we propose that low birthweight may be a risk factor to ARDS in the pediatric population.

The two objectives of our proposal are:

  • To use an rat model of low birthweight to test the effects this may have on the lungs after birth.
  • To test if rats with low birthweight are more susceptible to developing lung injury.

Both these objectives will investigate male and female animals.

We will use a rat model of low birthweight induced by feeding the pregnant rats a low protein diet. The lung injury will be induced by exposing young male and female rats to sepsis, which is an infection that commonly lead to ARDS. Our laboratory specializes in lung physiology and biochemistry, thus the offspring of these animals are examined using a variety of techniques related to lung function and injury.

The main novelty of our studies is the utilization of animal models that accurately reflect the human conditions; specifically, we investigate the effect of low birthweight on lung injury in the pediatric male and female population. As there is no “one-size-fits-all” pharmacological therapy for patients with ARDS, our experiments will help in the development of future studies that uses a more personalized approach to treatment, taking in consideration the sex of the patient, the age and the presence of potential risk factors. Ultimately, our studies may contribute to the improvement of the mortality and morbidity associated with sepsis-induced ARDS.

Our proposal focuses on ARDS which is a pulmonary condition with a high mortality rate. Our studies may ultimately contribute to the design of new therapeutic approaches for this disease based on a better understanding of the factors that influence the development and progression of this condition.


Dr. Bryan Heit
Bacterial Modulation of Alveolar Macrophage Efferocytosis During Pneumonia.
Amount Awarded: $49,550

Pneumonia – infection of the lungs by pathogens such as bacteria – are a major cause of hospitalization and death among Canadians. Many pneumonia survivors experience a severe and lasting loss of lung function; the consequences of this range from long-term disability to death. In fact, the likelihood of a pneumonia patient dying from a post-pneumonia complication is higher than the likelihood of a patient dying from the complications of a heart attack or stroke. Clearly, better treatments for recovering lung function are required for pneumonia patients, both to restore normal lung function after disease, and to prevent the deaths resulting from post-pneumonia complications.

We and our collaborator have recently discovered that the ability of lung macrophages to remove dead and dying cells – a process termed ‘efferocytosis’ – is required for the recovery of lung function, with poor efferocytic capacity resulting in a poor recovery of lung function. We have also discovered that Staphylococcus aureus, a bacterial pathogen responsible for many cases of pneumonia, can use dying lung cells as “Trojan horses” to infect other cells, and in doing so, creates the efferocytic defects that lead to poor recovery of lung function. In this proposal, we will determine how lung macrophages process Staphylococcus aureus encountered as a “Trojan horse”, and how encountering “Trojan horse” pathogens lead to defects in efferocytosis.

We have developed a model system of Staphylococcus aureus “Trojan horse” infection which results in macrophages with efferocytic defects similar to those seen in human pneumonia patients. Using this model and live-cell microscopy, we will investigate how Staphylococcus aureus taken up as “Trojan horses” are processed by lung macrophages, specifically investigating whether the macrophage treats these “Trojan horses” as though they were a dying cell or a pathogen. Secondly, we will quantify which genes are active in macrophages after taking up these “Trojan horses” in order to understand how the macrophages are “programmed” to be poorly efferocytic. This will allow us to understand the processes that lead to a loss of efferocytic function and failed lung repair in pneumonia patients.

The discovery that the efferocytic capacity of lung macrophages determines the recovery of lung function following pneumonia was made less than a year ago by my collaborator. To our knowledge, the model system we have developed exists no where else in the world. As such, we are in the unique position to investigate both “Trojan horse” infection in pneumonia, and the resulting loss in efferocytic capacity of lung macrophages.

This proposal is directly focused on understanding how and why lung function is lost following pneumonia. This work may lead to treatments which restore efferocytosis in pneumonia patients, thereby preventing the loss of lung function that is an all too common result of pneumonia. This would directly improve the lung health of the approximately 11,000 Canadians who die of pneumonia and the resulting loss of lung function each year.


Dr. Kjetil Ask
The role of DECTIN-1 in pulmonary fibrosis
Amount Awarded: $50,000

Lung fibrosis is a disease that often proves fatal 2-3 years post-diagnosis. It affects about 15,000 Canadians with approximately 6,000 new diagnoses made each year. As the disease progresses, scar tissue accumulates in the lungs, making breathing difficult and then impossible. There are few treatment options for this type of disease. The reason for this is likely because we do not know well how people develop the disease in the first place and we know very little about how and why the scarring is out of control. If we can better understand which cells are responsible for making the scars and how they produce the scars, then we may be able to stop the scarring process so patients can breathe better and live longer.

Our project aims to understand the molecular processes leading to the generation of a specialized cell type called the macrophage. We think that under certain circumstances, macrophages are very important in the scarring process and that they contribute to the formation of the scars in the lungs. Our main objective is to provide scientific evidence that they are truly involved and required for the scarring process, and to better understand how they do it. If we can increase our understanding of the molecular mechanisms driving this process and demonstrate that this cell is critical for the scarring process, then we can perhaps stop the scarring process and help patients to breathe better and improve their quality of life.

We have already identified a key molecular mechanism and what we think is the most important cell – the macrophage. We have also identified a unique marker of this important cell. Here, we will continue this work and clarify if the unique marker is also actively involved in the fibrotic process. By examining the specific role of this molecule, we believe we can identify a novel therapeutic target required in the scarring process.

Our project is unique because we are exploring a molecular mechanism that is well-known in other cell types but that has never been shown to be important in macrophages or in lung fibrosis. Our research will help to further understand the role of activated macrophages in pulmonary fibrosis. Though our projects described in this application are focused on lung fibrosis, these mechanisms are likely to have similarities with those in other chronic lung diseases that have components of scarring associated with their disease such as asthma (airway fibrosis) and COPD (bronchial fibrosis). If we can further our understanding on how macrophages contribute to the scarring process and if they are essential for this process, we can perhaps find new treatment options for patients with fibrotic lung disorders.


Dr. Clodagh Ryan
Effect of Continuous Positive Airway Pressure on Cardiopulmonary Function in Pulmonary Hypertension.
Amount Awarded: $50,000

Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary condition with a female predominance affecting approximately 50 per million. It is caused by progressive narrowing and constriction of the small pulmonary vessels, leading to an increase in the afterload to the naïve right ventricle (RV), eventually leading to RV failure and death. Significant advances in the treatment of PAH have occurred over the last 10 years with the development of a number of PAH specific medications. These medications improve morbidity and exercise tolerance and can lead to a reduction in RV afterload and improvement in RV function. Recent registry data show an improvement in survival with current medical therapies from a 3 year survival of 34% in the 1980’s to 70 – 83% in treated patients today. As survival improves in this population, there are increasingly older patients with more comorbid illnesses and obesity. Sleep apnea is more prevalent in those with obesity and occurs in approximately 20 – 40% of patients with PAH. Obstructive sleep apnea events generate negative intrathoracic pressure, intermittent hypoxia and arousals which can adversely impact heart function. Continuous positive airway pressure (CPAP) is the gold standard treatment of obstructive sleep apnea. Nevertheless, it is recognized that CPAP can have both positive and occasionally negative impacts on heart function depending on the underlying cardiac condition. In heart failure patients, the preload- and afterload-dependent status will determine the cardiac output responses (increase or decrease). Therefore, CPAP could improve and augment right heart function in patients with PAH. However, no previous studies have specifically examined the impact of CPAP in those with PAH, nor the acute effects of obstructive apneas.

Objectives of the project:

  • To evaluate the acute effects of CPAP on the right heart function in patients with PAH compared to healthy controls.
  • To assess the acute effects of simulated obstructive apneas on right heart function in patients with PAH compared to healthy controls.

Patients with pulmonary artery hypertension who consent and are undergoing a clinically necessary right heart catheterization test, and healthy volunteers will be tested to determine the impact of CPAP and simulated obstructive apneas on RV function in the catheterization laboratory.

Neither the acute impact of CPAP on RV function, nor the effect simulated obstructive apneic effects has been evaluated in patients with pulmonary artery hypertension. Our project is evaluating a device therapy that if found to be beneficial has the potential to provide an additional treatment that could significantly improve lung-heart function for those suffering from PAH. All too often due to deteriorating lung function these patients become oxygen dependent and exercise limited. CPAP if beneficial is readily available and relatively inexpensive therapy.


Dr. Mandeep Singh
The variability and impact of segmental neck and leg fluid volume shifts on upper airway collapse and obstructive sleep apnea (OSA) severity in surgical patients with OSA– A two-center, prospective cohort study
Amount Awarded: $49,984

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, associated with repeated upper airway collapse and reduced blood oxygen levels. At the time of surgery, exposure to general anesthesia and narcotic medications can lead increased respiratory problems poor surgical results, respiratory failure and even death. Experts from surgery, anesthesia and the perioperative team have established good practices and guidelines called the Enhanced Recovery After Surgery (ERAS). It is recommended that fluid administration should be done with care but no specific criteria for OSA patients is laid out. We know that increased lung fluid volume leads to problems in oxygen levels in blood and breathing problems especially after chest and abdominal surgeries. Similarly, upper airway collapse can occur more frequently in OSA patients as increased fluid in neck structures can compress the upper airway, leading to worsening of OSA and increased respiratory complications following surgery.

Our study objectives are to measure changes occurring in the fluid volumes in the neck, legs and total body, and find a relation between these changes and worsening of obstructive sleep apnea in patients undergoing general anesthesia and receiving intravenous fluids.

We will include 50 patients undergoing various types of surgeries (except heart, spine or neck surgeries), and measure fluid volumes using bioelectrical impedance technology, before and after surgery. Patients will also undergo portable sleep studies to look at the impact on their OSA status. All the measurements and study events will be collected in a well detailed, prospective fashion. We will also collect clinical findings such as respiratory complications associated with OSA patients, e.g. stay in the recovery room, respiratory failure, and stay in the intensive care unit.

In this novel study, we will extend our group’s previous research work evaluating the impact of fluid shifts on OSA severity. Our group has a strong track-record in screening, diagnosing, and evaluating perioperative outcomes of OSA patients. Furthermore, recently we have established a protocol to diagnose and screen OSA patients, as well as measure postoperative fluid measurements in patients undergoing surgery. Our study will be the first to evaluate and establish the relationship between fluid administration and worsening OSA severity in this patient population. Our findings will establish a key link between OSA worsening, increased postoperative respiratory complications in OSA patients and fluid changes that occur after surgery. Our findings will also inform the ERAS guidelines and establish evidence based standards in fluid management of OSA patients undergoing surgery.

OSA patients are exposed to increased risk of respiratory complications following surgery and anesthesia leading an increased burden of care, and poor clinical outcomes. The findings of our study will aim to minimize patients undergoing surgery from developing respiratory complications, enhance their postoperative recovery and result in improved overall lung health.


Dr. Tetyana Kendzerska
Obstructive sleep apnea and cancer development and progression: evidence from clinical and health administrative data
Amount awarded: $40,000

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder where repeated episodes of upper airway narrowing or collapse during sleep lead to disrupted sleep and periods of low blood oxygen levels. OSA may cause sleepiness, traffic accidents and predispose to serious health problems. Treatment for OSA exists, but it is not always tolerated or acceptable to patients. As a result of low blood oxygen level and disrupted sleep, OSA may increase the risk of cancer development and progression. Studies to date have not confirmed the possible link between OSA and cancer. Most studies published had to pool all types of cancer because they had too few new cases, potentially diluting the link with a specific type of cancer. If OSA is in fact a carcinogen and if treatment of OSA might prevent cancer, it would be another piece of the puzzle to understanding the origins of cancer as well as a possible avenue to prevent cancer.

The purpose of our study is to evaluate the link between OSA severity, as measured by the number of pauses in breathing or blood oxygen level in sleep, and development of new cases of cancer (all and by different subtypes) or dying from cancer. We will also assess which patients with OSA are at the higher risk of cancer or dying from cancer.

To do this, we will use clinical data from four large comprehensive sleep databases (~ 30,000 individuals) together with high quality validated information routinely collected during the course of universal health care delivery in Ontario (Canada). Individuals will be followed for more than 10 years based on their contacts with the health care system to identify all new cancers and deaths. As a result, we will be able to confirm the link between OSA and cancer and to identify individuals with OSA at higher risk.

We are uniquely positioned to investigate the link between OSA and cancer, as we have access to multicenter exposure data, high quality outcome data and relatively complete longitudinal follow-up data. Knowledge of a patient’s risk will empower clinicians and patients to make informed decisions about treatment of OSA and may assist in advocating for better care and research into new therapies for OSA by adding to the known consequences of OSA. This information will support a discussion between patients and physicians on the management options and follow-up strategies available; it will allow clinicians to identify patients who benefit the most from treatment. It may also motivate improvements in treatment adherence ultimately improve patient outcomes and the quality of care for these patients.


Dr. Jim Jian Sun
Restoring macrophage function against tuberculosis
Amount Awarded: $50,000

Tuberculosis (TB), a contagious respiratory disease of the lung caused by inhaling the bacterium Mycobacterium tuberculosis (Mtb) is responsible for over 2 million deaths each year. While antibiotics are usually effective in treating TB, the emergence of drug resistant Mtb strains coupled with the lack of new anti-Mtb drugs renders treatment increasingly difficult. Inhaled Mtb are engulfed by special cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to deprive their ability to kill the bacteria, which leads to disease progression. We have identified a host cell protein (PPM1A) that Mtb hijacks to shut down the killing function of these immune cells.

Our objectives are now to understand how this protein controls the ability of our immune cells to kill invading bacteria, and to identify drugs that can target this protein to restore the normal function of macrophages. This approach to target host cells instead of the bacteria will have the potential to boost the ability of our immune cells to eliminate Mtb, which can be developed as a unique and alternative treatment strategy against TB. Importantly, because host-directed therapy is aimed at boosting the body’s own immune system, the results from this research will be applicable to a variety of other infectious bacterial diseases that affect lung health such as pneumonia.

The advancement of this strategy is critical as it is becoming increasingly clear that the goal of a complete eradication of Mtb is unlikely if we strictly depend on antibiotics targeting the bacterium. A host-directed therapy approach holds immense promise for the development of adjunctive TB therapy in the future because this strategy would circumvent major problems associated with the development of antibiotic resistance. As such, the proposed research aligns with the mission of the Canadian Lung Association to promote lung health by preventing, treating, and ultimately eliminating deadly lung diseases such as TB. The threat of TB in our country persists as multi- and extreme-drug resistant Mtb strains are now common and increasingly cause infections even in developed countries, which render many front-line drugs inadequate. Alarmingly, a recent statement by WHO strongly warns that efforts to beat tuberculosis fall far short (http://www.reuters.com/article/us-health-tuberculosisidUSKCN12D1YK). The proposed research will thus become an essential piece of the puzzle to advance host-directed therapy efforts against TB with the prospect of eliminating this deadly disease, a long-standing mission of the Canadian Lung Association.