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2005-2006

The Lung Association and its medical section, the Ontario Thoracic Society (OTS), work to support and promote respiratory health through medical research and continuing education. This Research Update provides a brief summary outlining the 15 projects funded by The Lung Association during the 2005-2006 year in Ontario. The OTS is responsible for reviewing and approving grants as well as ensuring 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 (2005-2006)

Acute Lung Injury (ALI) →
Asthma →
Chronic Obstructive Pulmonary Disease (COPD) →
Lung Disease →
Lung Infection→
Sleep Disorders →
 


Acute Lung Injury (ALI)

Dr. James F. Lewis
Lung-Liver Interactions in ARDS and Multiorgan Failure

Our research has focused on evaluating the role of the surfactant system (the inner layer of the lung allowing us to breath with minimal effort) in diseases that injure the lung. One important and common disease causing respiratory distress is pneumonia, which if severe enough, can lead to respiratory failure and death. An interesting observation in these latter groups of patients, is that they usually develop inflammation throughout their whole body, and die of multiple organ failure (MOF) even though the initial inflammation and infection was in the lung. We want to determine how this happens so that we can target the lung with therapy (i.e. exogenous surfactant) and prevent death. We propose to set up a unique model of lung inflammation where we can determine exactly what comes out of the lung going into the circulation. This is done by isolating a lung from a lung-injured mouse and inserting catheters so we can collect the fluid coming directly out of the injured lung. We will then infuse this material into a normal mouse liver and perform a series of sophisticated studies to determine if this lung fluid has harmful effects on liver function. We will also use genetically altered animals to determine the role of a specific surfactant protein (SP-A) in this paradigm. We will also administer an exogenous surfactant preparation into the animals’ lungs shortly after they develop lung injury to see if we can prevent the release of mediators from the injured lung and thereby preventing organ (liver) failure. Ultimately, these studies will lead to new and innovative treatments for these patients directed at the lung which will prevent other organs from failing, and their death.

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-flammatory 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 of animal models. Our long-term goal is to selectively inhibit production of PTX3 from lung 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. 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.

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. Zhou Xing
Regulatory Role of TNFa in Immunity and Immunopathology during Influenza Viral Infection in 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 immunopathology still remain to be understood. In our current proposal, we will use an experimental model system to address the role of an important immune modulatory molecule called tumor necrosis factor alpha, in anti-influenza immune responses and lung tissue 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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Asthma

Dr. Manel Jordana
Immune-Inflammatory and Reparative Responses to Chronic House Dust Mite Exposure in Mice

We know that asthma is a chronic inflammatory disease, and that this chronic inflammation leads to structural abnormalities of the airways such as fibrosis, a process akin, in some respects, to scarring of the skin. The mechanisms underlying the process are poorly understood. In addition, the extent to which this process can be attenuated or even reversed, either spontaneously (upon cessation of allergen exposure) or therapeutically (through the administration of drugs) remains largely to be elucidated. While investigating this process in humans is extremely important, human research provides only a snapshot of what is surely a complex and dynamic process. We have established a unique experimental model in which mice are exposed for a prolonged period of time (up to seven weeks) to a house dust mite extract. Under those conditions, mice develop maintained eosinophilic inflammation and structural abnormalities of the airways similar to those observed in human chronic asthma. Using this model, we will perform a series of studies designed to inform about critical molecules that are involved in this process. We will also perform detailed studies to learn about the nature (severity and reversibility) of the reparative/fibrotic response that occurs under conditions of even extended exposure. These studies cannot be performed in humans; yet, they will provide novel knowledge with, in our view, great clinical significance and relevance.

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Chronic Obstructive Pulmonary Disease (COPD)

Dr. Shawn Aaron
Optimal Therapy of COPD to Prevent Exacerbation and Improve Quality of Life: A Randomized, Double-Blind, Placebo-Controlled Trial

Patients with chronic obstructive pulmonary disease (COPD) are often chronically short of breath. There are several new inhaled medications that have recently become available which may be useful for treatment of COPD. It is unclear, however, whether combining these medications may make them more effective than when they are used individually. The purpose of this study is to perform a controlled clinical trial to determine what combination of inhaled medications best prevents exacerbations and improves quality of life in patients with COPD.

Dr. Jane A.E. Batt
Molecular Mechanisms of Skeletal Muscle Atrophy in Lung Disease

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are progressive lung diseases. People with these diseases suffer from chronic shortness of breath and skeletal muscle wasting and weakness, which limits their ability to carry out the everyday activities that most healthy individuals take for granted. It is unclear in the medical and scientific literature why and how this muscle program develops. In this study, we hope to determine what causes the muscle wasting\weakness in people with severe COPD and IPF, and to begin to understand how it develops. We will achieve this goal by studying the muscle in people with advanced chronic lung disease, looking specifically at the rate and mechanisms of muscle breakdown and the potential molecular mediators. We believe our findings may lead to future therapies to prevent or treat the debilitating muscle wasting and weakness that occurs with chronic lung disease.

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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. Denis O’Donnell
Effects of Thoracic Restriction and Obesity on the Ventilatory Response to Carbon Dioxide

Restrictive lung disease is a common health problem among Canadians. It is associated with reduced elasticity of the lungs and chest wall resulting in a decrease of lung volumes. These functional changes may have serious effects on exercise capacity, breathlessness and quality of life. The prevalence of obesity in Canada has reached epidemic proportions and its effect on the respiratory system is similar to that observed in restrictive lung disease. Therefore, the proposed studies will use a novel approach to study the effects of restrictive lung disease and obesity on ventilatory function. A group of fifteen healthy men will perform a special breathing test with and without a restrictive vest that limits movement of the chest and stomach. A group of fifteen obese men will also be studied without the vest. The effects of the restrictive vest and obesity on pulmonary function will be examined. These studies will provide a new test approach for the study of restrictive breathing mechanics in patients with different forms of restrictive lung disease and important information regarding the causes of reduced functional capacity and breathlessness in obesity and restrictive lung disease, respectively.

Dr. Martin Robert Stämpfli
Impact of Cigarette Smoke on Airway Inflammation and Tissue Remodeling Elicited by Common Environmental Allergens in Mice

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 active smoking and exposure to second-hand smoke impact 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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Lung Infection

Dr. T. Karnauchow
Viral Etiologies of Bronchiolitis in a Large Outpatient Cohort (Short title – Viral Etiology Study)

Bronchiolitis is the most common respiratory tract disease in infants under one year of age, and is a significant cause of illness in young children. Respiratory Syncytial Virus is the most commonly identified infectious organism in children with bronchiolitis. The role of other viruses in this disease is less clear: some very common respiratory viruses may also be important. In addition, since 2001, 2 new respiratory viruses have been discovered: their involvement in bronchiolitis is still unclear. Finally, more than 1 virus is often found in affected children, but the significance of this with respect to the severity of disease is unknown. We propose to study a large group of children from across Canada, to determine the roles of several different viruses, both old and new, in brochiolitis, and to examine the impact of multi-virus infection on the course of illness. This will be the most comprehensive study of respiratory viruses performed in Canada.

Dr. Amy Catherine Plint
A Study to Derive a Clinical Decision Rule for Predicting Severe Bronchiolitis

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.

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Sleep Disorders

Dr. James Duffin
The Effects of Repeated Hypoxic Episodes and Arousals on the Chemoreflex Control of Breathing in Sleeping Humans

Patients with obstructive sleep apnoea (OSA) experience repeated episodes of airway obstruction, leading to increases in carbon dioxide (CO2) and decreases in oxygen. The chemoreceptors, which sense the changes in oxygen and carbon dioxide, provide the only control of breathing during sleep, and so they act as a protective reflex and produce an arousal to clear the obstruction. Unfortunately, the control of breathing in OSA patients is different from normal and exacerbates the OSA condition by worsening the obstructive episodes and increasing the strength of the arousals. The arousals affect the cardiovascular system, and over stimulation leads to hypertension and other cardiac problems. These considerations raise a fundamental question about the control of breathing in OSA patients: Is the altered control of breathing in OSA patients a consequence of the OSA condition, or an inherent characteristic predisposing these patients to OSA? I hypothesise that some aspect of the repeated obstructive episodes experienced by OSA patients alters respiratory control and that this is a normal physiological process. But which aspect of the obstructive episodes produces the changes? I hypothesise that it is probably the low oxygen, but it might also be the arousals. I propose to separately replicate the lowered oxygen and arousal aspects of the OSA in normal healthy subjects during sleep, so as to determine the effect of each of the factors on respiratory control. I will then find out if the changed respiratory control in OSA patients is a result of their condition, that is, a normal consequence of the obstructive episodes, or a predisposing factor. A better understanding of the changes in the control of breathing in OSA can help to devise treatments to prevent of reverse them.

Dr. Michael Fitzpatrick
Mandibular Position and Upper Airway Resistance During Sleep in Normal Subjects

The resistance of the throat area, and the tendency for the throat to obstruct during sleep, are much greater when mouth breathing than when nose breathing. Subjects with normal nasal resistance tend not to mouth breathe during sleep. However, patients with obstructive sleep apnea tend to have higher nasal resistance than normal subjects, and may even have complete nasal obstruction. Many of these patients are forced to mouth breathe during sleep, and this is a significant factor in causing their sleep apnea. During sleep, even in normal subjects, the jaw opens. This jaw opening is even more pronounced in patients with obstructive sleep apnea. Jaw opening during sleep increases the propensity of the upper airway to collapse. It is not clear whether the reason for increased resistance in the throat area, and increased tendency to obstructive sleep apnea, while mouth breathing, is the airflow route (mouth rather than nose) or the increased jaw opening that would be expected to occur with mouth breathing during sleep. In addition, it is unclear how much of the increase in the resistance of the throat that occurs during sleep in normal subjects is a result of movement of the jaw. This proposal will attempt to answer these questions by (1) fixing the jaw position with an oral appliance and then comparing upper airway resistance during sleep while nose-breathing and while mouth-breathing, and (2) allowing the subject to breathe normally and comparing upper airway resistance with the mandible fixed in position and with the mandible free to move.

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