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2007-2008

The Lung Association and its medical section, the Ontario Thoracic Society (OTS), work to promote respiratory health through medical research and continuing education. This Research Update provides a brief summary outlining the 8 projects funded by the Lung Association during the 2007-2008 year in Ontario. The OTS relies on experts from across Canada to review the proposals and is responsible for approving the grants and allocating the research budget. OTS also ensures that research material is distributed into hospitals, clinics and other health care settings. The Lung Association is proud of the class of academic excellence currently being supported in Ontario and will strive to carry forward this high level of excellence to improve the respiratory health of Canadians.

Research Funded (2007-2008)

Acute Lung Injury (ALI) →
Chronic obstructive pulmonary disease (COPD) →
Lung Disease →
Research Grant Awards →

 


Acute Lung Injury (ALI)

Dr. Haibo Zhang
Critical Role of Bone Marrow-derived Mesenchymal Stem Cells in the Repair of Lung Injury

Lung structural damage or acute lung injury 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, is a major cause of death in critically ill patients. The lung surface contains cells with properties of bone marrow stem cells. The bone marrow stem cells can become specialized lung cells. There is evidence that acute lung injury is derived from a lack of stem cells. In a pilot study of an acute lung injury model in mice, we demonstrated that administration of bone marrow-derived stem cells can prolong animal survival before the stem cells are transformed into lung cells. The aims of the present CLA/OTS grant proposal are to examine the hypothesis that the bone marrow-derived stem cells release specific soluble proteins that protect lung surface from injury. Our study will provide potential clinical applications that may lead to new treatment strategies for lung diseases.

Dr. Diane Lougheed
Physiology of Cough in Asthma: Sensory-mechanical Responses to High-dose Methacholine in Asthma, Cough Variant Asthma and Eosinophilic Bronchitis

Cough is a common, disruptive and at times disabling symptom, which often prompts patients to seek medical attention. Determining the cause(s) of chronic cough can be challenging, and costly. Asthma and other airway disorders are among the most common causes of chronic cough; and cough can be the sole symptom of asthma. Little is known about why some patients with asthma primarily cough and do not develop the other symptoms of asthma such as shortness of breath or wheeze. Improved understanding of the reasons for these different manifestations may lead to new and more effective treatment strategies. We have noticed differences in pressure measurements inside the chest in patients who mostly cough during a simulated asthma attack, which might be part of the explanation for varying symptoms. This study will compare lung mechanical responses during induced airway narrowing between typical asthma, cough variant asthma and an airway inflammatory disorder that is not asthma.

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Chronic Obstructive Pulmonary Disease (COPD)

Dr. Matthew Buchanan Stanbrook
Death in Chronic Obstructive Pulmonary Disease (COPD) in the Ontario Population

Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in Ontario, yet most treatments currently available for COPD don’t seem to reduce mortality. This is a huge public health problem because COPD is becoming more common. One possible explanation is that current treatments actually do reduce mortality, but existing studies (such as randomized trials) haven’t been able to show it because they’re too small, studied too short a time period, or selected patients who are not typical of most people with COPD. Alternatively, many deaths in COPD may occur from causes that COPD medications don’t treat (such as heart attacks). Both these possibilities could be addressed by using information from Ontario’s administrative computer databases. Since Ontario has a universal public health care system, health care use by virtually all residents of Ontario has been recorded going back as long as 17 years. We can therefore learn about disease trends by studying the entire population. This has been done successfully in Ontario for conditions such as heart disease and diabetes and we plan to do the same for COPD. In order to do this, however, we need to be sure that the information in the database correctly identifies patients with COPD. We therefore propose to validate the database information by comparing it with information from a representative sample of clinical charts from family doctors’ offices, with results of lung function tests, and with other sources of information that identify people with COPD. Successful validation of the databases would immediately allow for population-based studies of COPD in Ontario, thereby creating one of the most powerful data sets in the world for studying COPD.

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Lung Disease

Dr. William Matthew Binnie
Role of RegIIIgamma in Defence of the Respiratory Tract

In the proposed research I will investigate the role of a small protein named regIII gamma that is secreted by the cells lining the respiratory tract and that can kill some types of bacteria on contact. I believe that this protein may have a role in protecting the lungs, nose and middle ear from bacterial infection. I will test this idea using regIIIgamma knockout mice that I have engineered. These mice cannot produce regIIIgamma protein, so if this protein plays an important role in defending the respiratory tract from infection the mice should be more easily infected, or once infected they should become sicker than, than normal mice.

I would also like to explore the possibility that regIIIgamma has a direct effect on the ability of cells lining the airways to re-grow following an airway injury. I will again test this idea using regIIIgamma knockout mice, investigating their susceptibility to a chemical called naphthalene, which causes may airway lining cells to die off, forcing the remaining cells to grow and migrate to replace them. If regIIIgamma is important for this response then the knockout mice should show increased susceptibility in this model.

I am hopeful that these studies will inform us about the role of this intriguing protein in the lungs and upper respiratory tract. If regIIIgamma can be shown to protect mouse lungs from bacterial infection then I will be important to see if the human version of this protein plays a similar role. This is a basic biological question, but it may have implications for why some individuals may be more susceptible than others to pneumonia, sinusitis and ear infections. Moreover, in the future, drugs designed to copy the activity of regIIIgamma might be developed to treat respiratory tract infections. Finally, if regIIIgamma affects growth of the airway lining cells then it will be important to determine whether this molecular pathway is involved in the uncontrolled proliferation of airway cells that occurs in lung cancer.

Dr. Chung-Wai Chow
The Role of Syk and Ezrin in HRV Endocytosis and Signalling

The human rhinovirus (HRV) is the most common acute infection in humans, and causes the common cold. While cold symptoms are mostly self limited in healthy individuals, HRV infections have a significant economic impact, with an estimated economic loss of $US40 billion per annum due to loss of productivity and absenteeism.

In select patient populations, particularly those with underlying lung diseases, HRV infections lead to significant morbidity. HRV infections are the most common cause of hospitalization for wheezing in children outside of the respiratory syncytial virus season. In patients with asthma and chronic obstructive lung disease (COPD), HRV infections are associated with (and may be responsible for) ~80% and ~50% exacerbations of asthma and COPD, respectively.

Due to significant differences amongst the 100+ HRV subtypes, there is little cross-protection following infections, and development of effective vaccines is difficult. However, most (>90%) HRV to ICAM-1 is a key initiating event that not only permits viral entry but independent of viral replication, is sufficient to initiate the profound inflammatory response observed in asthma and COPD exacerbations.

My lab has identified an immunoregulatory protein, Syk, to be an early proximal molecule that regulates expression of IL-8, an inflammatory mediator highly associated with asthma exacerbations, following HRV-ICAM-1 binding. The mechanisms that regulate Syk activation are not known and are subject of the experiments outlined in the current proposal. Because Syk is known to regulate receptor-mediated uptake of extracellular materials, we will also evaluate its role in mediating HRV cell entry. Our goal is to identify molecules that can be targeted when developing novel therapies to treat HRV infections and prevent serious complications such as exacerbations of asthma and COPD.

Dr. Martin Kolb
Circulating Mesenchymal Progenitor Cells in Patients with Chronic vs Acute Lung Disease

Emphysema and fibrosis are chronic lung diseases which are a major burdent to our health system. They are characterized by loss of functional lung tissue. In emphysema, the building material (“matrix”) between lung structures is lost, resulting in the formation of large air bubbles. In contrast, in fibrosis an increase of this matrix is found and results in excessive scarring. The matrix is amongst others produced by cells called myofibroblasts. They are known to be over-active in fibrosis and make too much matrix, and it might well be that thy are not active enough in emphysema. It is, to date, unclear where these lung cells come from but three ideas are discussed: (1) they derive from the lung by growth and division of already present myofibrobasts; (2) they originate from the lung by transformation of cells that cover the inner surface of the lung (termed epithelial cells) into myofibrobasts; and (3) they come into the lung by being recruited from cells that are circulating in the blood stream I(these cells are called “mesenchymal progenitor cells” or short MPC).

We are able to measure MPC in the blood in health and sick individuals. This project aims to examine the number of these cells in the blood of patients with diferrent lung diseases to better understand their biological role. We will count the cells in patients with acute disease such as pneumonia, as well as chronic lung disease, both emphysema and fibrosis. We will also examine if the number of these cells in the blood is related to the severity of disease. One important question would be: does someone with higher than normal levels of MPC in the blood develop excessive scarring and fibrosis while someone with fewer than normal develops loss of matrix and emphysema? Further, we will analyse the features of these MPC in a culture dish and examine if they are different between the disease groups. Once identified and characterized, novel drugs could be designed that either suppress (e.g. in fibrosis) or stimulate (e.g. in emphysema) MPC to better treat these chronic lung diseases.

Dr. Andrew Leask
Protein Kinase C Epsilon: A New Target for Drug Intervention in Pulmonary Fibrosis

One of the major causes of deaths in Canada is lung fibrosis, which is caused by excessive scarring. The scarring is caused by the abnormal presence of a particular type of cell, called a myofibroblast, within the scar tissue. This cell produces too much of a protein called collagen. Also, the myofibroblast pulls on (contracts) collagen excessively. The result of the action of the myofibroblast is therefore a tight scar, which blocks normal lung function by blocking efficient gas exchange resulting in a failure to breathe properly (asthma). This condition is worsened by smoking. In diseases such as systemic sclerosis (scleroderma) or idiopathic pulmonary fibrosis, this scarring can result in death. Indeed, the main cause of death in scleroderma patients is lung fibrosis. My goal is to block the function of the myofibroblasts but not to block the function of normal cells. The key protein that causes the myofibroblast to contract the collagen is called A-smooth muscle actin (A-SMA) appears in a cell as cables spanning the length of a cell. These cables cause the cell to contract the collagen. My goal is to block the contraction of collagen by myofibroblasts by interfering with the ability of the A-SMA cables to form. My idea is that a protein called protein kinase C epsilon (PKCy) is specifically required for the formation of A-SMA cables, but is not required for normal cell function and therefore that blocking the action of PKCy would be a good strategy to combat lung fibrosis. In addition, since many other diseases including cardiovascular disease, diabetes, caner and liver cirrhosis have significant fibrotic components, I believe that my research will have wide-ranging implications for treating these diseases as well.

Dr. Martin Robert Stampfli
Impact of Cigarette Smoke on Immune Inflammatory Processes and Tissue Remodeling Elicited by Surrogate and Common Environmental Allergens

Smoking-related diseases are one of the major causes of suffering and death in Canada and worldwide. The organ most directly affected by cigarette smoking is the lung. It is well known that smoking is the main cause of lung cancer and the development of chronic obstructive pulmonary disease (COPD). The impact of smoking on asthma, however, remains poorly understood, although approximately 25% of asthmatic individuals smoke in developed countries. The objective of the proposed research is to investigate how smoking impacts immune-inflammatory processes associated with asthma. We believe that the proposed studies will further our understanding of the impact of cigarette smoke on lung health and lead to a better understanding of the pathogenesis of asthma.

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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. Matthew Binnie, University of Toronto/St. Michael’s Hospital
Role of REGIIIy in Defence of the Respiratory Tract
$44,976.00
Dr. Martin Kolb, Firestone Institute for Respiratory Health
Circulating Mesenchymal Progenitor Cells in Patients With Chronic versus Acute Lung Disease
$47,000.00
Dr. Andrew Leask, University of Western Ontario
Protein Kinase C Epsilon: A New Target for Drug Intervention in Pulmonary Fibrosis
$49,405.00
Dr. Diane Lougheed, Queen’s University
Physiology of Cough in Asthma: Sensory-Mechanical Responses to High-dose Methacoline in Asthma, Cough-variant Asthma and Eosinophilic Bronchitis
$49,600.00
Dr. Martin Stampfli, McMaster University
Impact of Cigarette Smoke on Immune Inflammatory Processes and Tissue Remodeling Elicited by Surrogate and Common Environmental Allergens
$47,950.00
Dr. Matthew Stanbrook, University of Toronto/University Health Network
Death in Chronic Obstructive Pulmonary Disease (COPD) in the Ontario Population
$48,339.00
Dr. Haibo Zhang, University of Toronto/St. Michael’s Hospital
Critical Role of Bone Marrow-derived Mesenchymal Stem Cells in the Repair of Lung Injury
$50,000.00
OLA/OTS Breathe New Life Award Amount Awarded
Dr. Chung-Wai Chow**, University of Toronto
The Role of Syk and Ezrin in HRV Endocytosis And Signalling
$50,000.00

 

** 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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