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2006-2007

Research Funded (2006-2007)

Acute Lung Injury (ALI) →
Asthma →
Lung Disease →
Lung Infection→
Other Areas of Investigation →
Research Grant Awards →

 


Acute Lung Injury (ALI)

Dr. Mingyao Liu
Pentraxin 3: A New Inflammatory Mediator In Acute Lung Injury

Despite great achievements gained in management of acute respiratory distress syndrome (ARDS), it remains the leading cause of death in critically ill patients. Acute inflammatory responses have been considered as one of the major underlying mechanisms. Blocking pro-inflammatory cytokines may reduce inflammation, but it may also halt bacterial clearance and increase the susceptibility to infection and mortality. Recent works have demonstrated that lung cells themselves play an important role in ARDS by releasing inflammatory mediators. Using microarray technique, we have discovered that human lung epithelial cells can produce a newly identified inflammatory mediator, called pentraxin 3 (PTX3). This protein has been found rapidly and significantly elevated in serum of critically ill patients. The objective of this study is to determine the cellular and molecular mechanisms of PTX3 production from lung epithelial cells and the role of PTX3 produced by lung epithelial cells in acute lung injury epithelial cells, which may attenuate tissue damage but preserve the functions of inflammatory cells for host defense in the lung. This novel concept may change the strategies for treatment of ARDS and acute lung injury.

Dr. Sanjay Mehta
Effects of Neutrophil vs Macrophage iNOS in Septic Human Endothelial Cell Injury

In critically ill patients, inflammation of the lung is a common clinical problem causing significant illness and a high (up to 50 %) risk of death. A variety of substances made by the human body contribute to lung inflammation, such as nitric oxide (NO). NO is made by many cells in the lungs. We have shown in mice that NO from certain cells, but not from all cells, may cause lung inflammation and lung injury. However, this has not been addressed in patients with lung injury. Thus, we propose to isolate cells from human lungs and blood, grow these cells in culture, and to study the role of NO from different cells in causing lung injury in humans. We will gain a better knowledge of the mechanisms and factors causing human lung inflammation and injury, which will lead to better, more effective, and targeted therapy in patients with lung injury.

Dr. Haibo Zhang
Regenerative Stem Cells in the Repair of Acute Lung Injury

Lung structural damage or acute lung injury is a major cause of death in critically ill patients as a result of many severe lung diseases, such as bacterial pneumonia, acute respiratory distress syndrome (one of the most severe fatal lung disease that is frequently associated with sepsis), and ventilator-induced lung injury. The lung surface contains cells with properties of bone marrow stem or progenitor cells. The bone marrow stem can become specialized lung cells. There is evidence that acute lung injury is derived from a lack of stem or progenitor cells. In a pilot study, we demonstrated that administration of bone marrow-derived stem cells can repair lung. The aims of the present CLA/OTS grant proposal are to extend the preliminary observation and to examine the mechanisms by which lung repair is associated with specific recruiting signals from injured lung that cause cells to grow and to heal the injured lung surface. We will use current cell and molecular techniques to attract stem cells to the injured sites in several mouse models of human lung diseases. Our study will provide potential clinical applications that may lead to new treatment strategies for lung disease.

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Asthma

Dr. Mark Inman
Goblet Cell Hyperplasia Rebound following Steroid Intervention

Respiratory diseases, including asthma, are often associated with chronic inflammation and structural changes of the airway. These structural changes, often termed airway remodeling, have been related to the degree of asthma symptoms, supporting the concept that remodeling may contribute to the severity of airway dysfunction. The airways of asthmatics are lined by injured cells, called goblet cells, that are believed to significantly contribute to structural damage of the airway and to asthma symptoms, including mucus plugging and airflow obstruction. Steroids have long been recognized as the most effective therapy for the treatment of asthma. However, we have recently observed that withdrawal of steroids treatment dramatically increases airway goblet cell numbers to levels significantly greater than if there was no steroid treatment. This rebound in goblet cell number raises the question as to whether individuals with respiratory disease are worse off following withdrawal of steroid treatment than those individuals that did not take steroids. The purpose of the proposed research is to perform a series of studies using our experimental model of allergic respiratory disease to determine if airway dysfunction is greater in mice following the withdrawal of steroids as compared to mice not treated with steroid. Additionally, we will investigate the characteristics and mechanisms of this goblet cell rebound following the withdrawal of steroids of steroid treatment. Ultimately, these studies may have critical implications on steroid treatment strategies for the management of respiratory diseases.

Dr. Jeremy Scott
Role Of Arginine Metabolism in Allergic Asthma

Asthma is a chronic disease of the airway that has increased in incidence over the last 40 years. Asthmatics experience persistent constriction and tightening of the airway when exposed to stimuli, such as cold air exercise and/or environmental allergens and pollutions. Despite significant advances in the treatment of asthma no cure has been found to date. Research has advanced to the stage that we are able to examine the contribution of specific genetic and biochemical pathways to the pathogenesis of asthma. One line of investigation involves the metabolism of the semi-essential amino acid, L-arginine, by the nitric oxide synthase and arginase biochemical pathways. There is a complex interplay between these two pathways that may be imbalanced in disease states, such as asthma. The arginase enzymes may play a role in asthma by two mechanisms: 1) by reducing the availability of L-arginine for the nitric oxide synthase pathway; reducing the amount of the relaxant molecule, nitric oxide, and 2) by increasing the proliferation of cells and deposition of collagen in the airways; resulting in increased obstruction of the airways. These investigations seek to examine the role that the arginase enzymes play in pathogenesis of asthma. The result of these investigations may provide new therapeutic approaches to treat asthma.

Dr. Susan Tarlo
Impact of Mainstream and Environmental Tobacco Smoke on Allergen-Induced Airway Inflammation and Tissue Remodeling in Mice

Asthma and chronic bronchitis have been estimated to be related to workplace exposures in approximately 15% of those with these conditions. In many workplaces, symptoms and airway changes on pulmonary function tests have been associated with potential airborne exposures to endotoxin. This is a substance found in the walls of bacteria which can grow in animal care facilities, farming environments, metal working fluids (used as coolants), and in household dust. Even when bacteria are killed, the endotoxin remains in dust or liquids and can be inhaled in aerosols or dust. It can cause direct effects leading to inflammation, and may also act to increase the development of allergic response leading to asthma and allergic nose and eye symptoms. Currently there is not a good measure of endotoxin in the body from workplace exposures and studies to date have relied on general air sampling to detect this. Therefore it has been difficult to identify whether there is an individual threshold level of endotoxin in the body which may relate to airway disease. The current study will use a new measure of blood endotoxin levels and a measure of inflammatory cell activation in the nose, in animal care workers, to determine whether there is a threshold of endotoxin which is important in producing and inflammation and airway responses. Findings may be applicable to other workplace environments and might be relevant also to home exposures leading to asthma and allergic responses.

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Lung Disease

Dr. Chung-Wai Chow
Expression and Function of Syk Tyrosine Kinase in Pulmonary Epithelial Cells

The lung is completely lined with a layer of epithelial cells. While acting as a barrier that prevents indiscriminate entry of inhaled matter, the epithelium also performs vital functions such as exchange of O2 and CO2 and production of surfactant. Because the epithelial layer is in constant contact with the external environment, it is constantly bombarded with inhaled toxins, microorganisms and allergens. As such the epithelium has developed mechanisms to remove and destroy any harmful inhaled material. It actively participates in the innate immune response by producing cytotoxic mediators such as cytokines and reactive oxidants, and by recruiting leukocytes to further propagate the immune and inflammatory cascade. These protective mechanisms are highly regulated so that once activated, appropriate down-regulatory signals are also triggered to stop the immune and inflammatory response before tissue injury occurs.

When the system is dysregulated, tissue injury occurs. This is the cause of numerous lung diseases that include asthma, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) and pulmonary fibrosis.

The underlying molecular mechanisms that regulate the immune and inflammatory response of the pulmonary epithelial cells are not well understood. My lab has recently identified a key leukocyte immune regulatory molecule, Syk, in pulmonary epithelial cells. Our data suggests that it is involved in regulating the intracellular signals of the immune and inflammatory pathways. The current proposal outlines specific aspects of the function and regulation of Syk that will be studied in pulmonary epithelial cells.

By better understanding of the normal pathways regulated by Syk, we may be able to identify specific pathways that are dysregulated in inflammatory mediated lung diseases.

Dr. Steve Iscoe
Acute Effects of Hyperinflation on Diaphragm and Heart

Many patients with chronic pulmonary diseases (for example, asthma, bronchitis) suffer from acute episodes when the disease worsens. One of the hallmarks of these episodes is an increase in the lung volume at which these people breathe. Not only does this cause respiratory difficulty that, if severe enough, cause what is termed ‘respiratory failure’ but it may actually damage the heart. This is because the changes in pressure within the chest, along with the lower levels of oxygen and increased levels of carbon dioxide in the blood, all can impair the heart’s ability to contract. In the proposed experiments, I will force rats to breathe at an elevated lung volume and monitor the contractile function of the diaphragm and heart. To determine what cause the impaired contraction, I will compare these responses to those when the animals breath extra oxygen, when they breathe a gas mixture that results in the same blood levels of oxygen and carbon dioxide but at a normal lung volume, and when they are given drugs that block specific neural responses that help the heart respond to the low levels of oxygen and carbon dioxide. I will also monitor the release into the blood of proteins that indicate if the heart and diaphragm have been injured. These experiments will provide new information about the mechanisms responsible for recent reports of injury to the heart in patients with acute worsening of respiratory disease, even though they had no heart disease.

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Lung Infection

Dr. David Hwang
Role of the Pulmonary Microflora in Human Lung Transplantation

Lung transplantation is a treatment of last resort for a range of end-stage lung diseases. One major challenge facing lung transplant recipients is the body’s rejection of the transplanted lung. As a result, transplant recipients must take immune-suppressing drugs, to minimize immune attack of the lung. However, because this immune suppression significantly increases the risk of life-threatening infections, patients must be monitored for both rejection and infection, so that immunosuppression can be kept to a minimum. Unfortunately, due to the limitations of current lab tests, distinguishing rejection from infection can be difficult; yet, making this distinction is as critical, as incorrect diagnosis may lead to inappropriate, potentially dangerous treatment. Furthermore, current lab tests for infection tend to screen only for certain microorganisms, and may fail to identify new pathogens. In this application, we propose new strategies to characterize bacterial infections in patients undergoing lung transplantation, using highly sensitive methods developed through the Human Genome Project. We hope to identify new bacteria that are important in these patients and that may mimic rejection or result or result in undetected infections in those undergoing lung transplantation. We believe this work will allow physicians to better tailor immunosuppressive and antibiotic treatments to the needs of individual patients.

Dr. Amy Catherine Plint
Study to Derive a Clinical Decision Rule for Predicting Severe Bronchiolitis
(2nd year of 2005-2006 two-year award)

Bronchiolitis is a viral infection of the lungs that typically affects young children and results in cough, difficulty breathing, and wheezing. It is the most common disease of the lungs during the first year of life. While most children with bronchiolitis do well, a small proportion become very ill – requiring admission to intensive care units, support for their breathing with ventilators, have episodes where they stop breathing and some die. For emergency physicians who see many children with bronchiolitis each year knowing which children are at risk for such severe disease is important. It would allow physicians to determine which children must be admitted to hospital and specifically which children should be admitted to a children’s hospital for care.

Dr. Rudolf Veldhuizen
The Role of Tissue Inhibitor of Metalloproteinases-3 During Sepsis

Like any other organ, lung tissue is in constant turnover in a process that requires a delicate balance between tissue breakdown and formation. Many lung diseases are associated with an imbalance in these processes leading to either excessive degradation of lung tissue or tissue build up. Our goal is to study some of the enzymes and cells involved in this balance of lung tissue breakdown and build up, and how this balance is altered in sepsis, a disease caused by an infection in the bloodstream due to bacteria that affects the lung. Understanding these processes will ultimately help in designing new treatment strategies for diseases in which tissue turnover is impaired either towards degradation or towards tissue build up.

Dr. Zhou Xing
Regulatory Role of Tumor Necrosis Factor-alpha in Immunity and Immunopathology During Influenza Viral Infection in the Lung

Acute lung infection caused by influenza virus continues to be an important cause of morbidity and mortality, particularly of children, elderly people and those with chronic disease, in Canada and elsewhere in the world. Protection by flu vaccine is suboptimal particularly in high risk populations and, the mechanisms of immune regulation and tissue imunopathology still remain to be understood. In our current proposal, we will use an experimental modal system to address the role of an important immune modulatory molecule called tumor necrosis factor alpha, in anti-influenza immune responses and lung tissue in injury. Our studies will enhance our understanding of the mechanisms of immune regulation and immunopathology during influenza infection and help with the better design of anti-influenza preventives and therapeutics.

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Other Areas of Investigation

Dr. Karen Burns
Wean Earlier and Automatically with New Technology (The WEAN study): A Multicentre, Pilot Randomized Controlled Study

Weaning is the process during which mechanical ventilation is withdrawn and the work of breathing is transferred from the ventilator back to the patient. About 40% of the total time spent on mechanical ventilation is related to weaning. Minimizing exposure to invasive ventilation is an important goal of intensive care medicine. Prolonged periods of invasive mechanical support are associated with longer stays in the intensive care unit, the development of ventilator-related complications and escalating costs. Computerized or “Automated Weaning“ is a novel weaning method that continuously measures and adapts ventilator support to each critically-ill patient on a ventilator by frequently measuring and averaging 3 breathing parameters. In addition, this weaning system automatically assesses whether patients are ready to resume breathing on their own.

Preliminary research in Europe suggests that Automated Weaning reduces the time spent on the ventilator and in the intensive care unit with no increase in the risk of weaning failure. Therefore there is a strong rationale to support that Automated Weaning may be better than the current approach to weaning but additional evidence is required to change clinical practice and to establish whether similar result can be obtained in Canada where weaning, unlike in Europe, is a collaborative effort involving intensive care doctors and respiratory therapists.

Automated Weaning holds the promise of reducing the burden of illness imposed by prolonged ventilator supports, decreasing intensive care length of stay and improving important clinical outcomes. The aim of our study is to evaluate compliance with weaning and sedation protocols in a multicentre, pilot randomized controlled trial (RCT) comparing Automatic Weaning and Usual Weaning among intubated patients requiring at least 24 hours of invasive ventilator support. This 9 centre pilot will assess the feasibility of conducting a definitive weaning RCT comparing the alternative weaning strategies in Canada in the future. In addition, it will provide a structural framework in which the full study can be conducted.

Dr. Sherri Katz
Prevalence of Nocturnal Hypoventilation and Impact of Non-Invasive Ventilation on Children and Adolescents with Static or Progressive Neuromuscular Conditions

Background:
Breathing problems are a known and frequently fatal complication of neuromuscular disease, which first present at night. Treatment of this problem with nighttime non-invasive positive pressure ventilation (NPPV), a facemask that provides breathing assistance, has been shown to improve children’s oxygen exchange and increases survival in people with progressive neuromuscular disease and breathing failure. Recognition of sleep-related breathing problems is difficult, as symptoms are vague.

Research Questions:

  • How common are sleep-related breathing problems in children with neuromuscular disease? Can they be predicted from symptoms, lung function tests and/or tests of muscle strength?
  • Does NPPV improve oxygen exchange, and/or improve daytime function and quality of life in children with neuromuscular disease and sleep-related breathing problems?
  • What is the progression of nighttime breathing problems in children with neuromuscular disease without sleep-related breathing problems?

Design:
Part 1 is a screening study in which children will undergo questionnaires, lung function and muscle strength tests and overnight sleep study. The second part of the study will compare nocturnal oxygen levels, daytime function and quality of life measures at the start of the study and one year later.

Dr. Stacey Ann Ritz
Effects of Particulate Air Pollution on Airway Antigen-presenting Cells: Roles of Oxidative Stress and GM-CSF in the Activation of Dendritic Cells

Exposure to air pollution is known to cause a variety of effects on human health. Tiny particles of air pollution, invisible to naked eye, cause changes in the lung when they are inhaled. Some of these changes create conditions that are conducive to the development of immune responses, which could potentially trigger or worsen conditions such as allergy, asthma, autoimmunity, and diseases of the blood vessels. In our studies, we plan to examine the effects of particulate air pollution on dendritic cells in the lung, which are cells specialized to cause immune responses. In addition, we will test whether pre-treatment with an antioxidant or blocking the activity of a biological molecule (GM-CSF) can prevent these kinds of changes. These studies will help us to understand the mechanisms underlying the negative effects of air pollution, point to possible strategies to limit the damaging effects in susceptible individuals, and provide evidence in support of efforts to develop more sophisticated standards for air pollution emission.

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Research Grant Awards

All grants are awarded based on ranking by the national peer review process conducted by the Canadian Thoracic Society.

OLA/OTS Awards (alphabetically)
Amount Awarded
Dr. Karen Burns, St. Michael’s Hospital, Toronto 
Wean Earlier and Automatically with New Technology (The WEAN study): A Multicentre, Pilot Randomized Controlled Study
$38,111.40
Dr. Mark Inman, St. Joseph’s Hospital and McMaster University, Hamilton 
Goblet Cell Hyperplasia Rebound following Steroid Intervention
$44,972.10
Dr. Sherri Katz, Children’s Hospital of Eastern Ontario, Ottawa 
Prevalence of Nocturnal Hypoventilation and Impact of Non-Invasive Ventilation on Children and Adolescents with Static or Progressive Neuromuscular Conditions
$30,269.25
Dr. Mingyao Liu, University of Toronto 
Pentraxin 3: A New Inflammatory Mediator in Acute Lung Injury
$45,000.00
Dr. Sanjay Mehta, Lawson Health Research Institute, London 
Effects of Neutrophil vs Macrophage iNOS in Septic Human Endothelial Cell Injury
$45,000.00
Susan Tarlo, University of Toronto 
Use of a Chemiluminescent Assay for Endotoxin to Determine Nasal Exposure to Inhaled Occupational Endotoxin.
$43,650.00
Dr. Rudolf Veldhuizen, University of Western Ontario, London 
The Role of Tissue Inhibitor of Metalloproteinases-3 During Sepsis
$45,000.00
Dr. Zhou Xing, McMaster University, Hamilton 
Regulatory Role of Tumor Necrosis Factor-alpha in Immunity and Immunopathology During Influenza Viral Infection in the Lung
$45,000.00
Dr. Haibo Zhang, St. Michael’s Hospital, Toronto 
Regenerative Stem Cells in the Repair of Acute Lung Injury
$45,000.00
OLA/OTS/GSK Awards (alphabetically) Amount Awarded
Dr. Chung-Wai Chow*, University of Toronto 
(2nd year of 2005-2006 two-year award)
Expression and Function of Syk Tyrosine Kinase in Pulmonary Epithelial Cells
$48,000.00
Dr. Steve Iscoe*, Queen’s University, Kingston 
Acute Effects of Hyperinflation on Diaphragm and Heart
$40,067.10
Dr. Amy Catherine Plint*, Children’s Hospital of Eastern Ontario, Ottawa 
(2nd year of 2005-2006 two-year award)
A Study to Derive a Clinical Decision Rule for Predicting Severe Bronchiolitis
$47,421.00
Dr. Stacey Ann Ritz*, Northern Ontario School of Medicine, Sudbury 
Effects of Particulate Air Pollution on Airway Antigen-presenting Cells: Roles of Oxidative Stress and GM-CSF in the Activation of Dendritic Cells
$32,079.60
Dr. Jeremy Scott*, University of Toronto, Toronto 
Role Of Arginine Metabolism in Allergic Asthma
$43,650.00
Dr. Martin Stämpfli*, McMaster University, Hamilton 
Impact of Mainstream and Environmental Tobacco Smoke on Allergen-Induced Airway Inflammation and Tissue Remodeling in Mice
$44,055.00
OLA/OTS Breathe New Life Award    Amount Awarded 
Dr. David Hwang**, University Health Network, Toronto
Role of the Pulmonary Microflora in Human Lung Transplantation
$43,650.00

 

* The Ontario Lung Association and the Ontario Thoracic Society gratefully acknowledge the philanthropic and corporate leadership of GlaxoSmithKline (GSK) in enhancing research in obstructive lung disease by investing in the Grants-in-Aid program. This investment permits funding of grants above and beyond the normal value of the GIA budget provided by the Ontario Lung Association (OLA).

** The funds for the “Breathe New Life Award” are partly raised by the OTS members through the Top It Up! For Respiratory Research fund. This fund enhances the nationally reviewed and acclaimed Grant-in-Aid research competition and funds grants above and beyond the normal value of the GIA budget provided by the Ontario Lung Association (OLA).

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