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Dr. Haibo Zhang, University of Toronto
Human Neutrophil Peptide (a-defensins) and its Receptor: An Expanding Role in Our Understanding of Neutrophil-evoked Acute Lung Injury
In many human lung diseases such as bacterial pneumonia and acute respiratory distress syndrome (one of the most severe deadly lung diseases), a particular type of white blood cell, the neutrophil, migrates into the lung in vast numbers. Neutrophils are essential in fighting off infection in several ways, including by secreting toxic substances, such as human neutrophil peptides, also know as a-defensins. Although a-defensins can kill bacteria at normal concentrations, a-defensins themselves induce long injury. The proposed study will further this work. We will search for cell surface receptors that initiate the action of a-defensin in human lung. We will use lung tissue and cells from the specific gene (Toll like receptor4), mutant mice and normal human cells to examine the possible role of Toll like receptor(s) in initiating the biological action of a-defensins. Once the receptor(s) is cloned, the role of a a-defensins in lung diseases can be more clearly defined. Our study will provide potential clinical applications that may lead to new treatment strategies of inflammatory lung diseases.
Dr. Diane Lougheed. Queen’s University, Kingston
Symptom Perception in Asthma: Mechanics of the Plateau Response
Despite advances in medical knowledge about the causes and treatment of asthma, many patients suffer from persistent, severe symptoms and deaths still occur. One factor thought to contribute to asthma morbidity and mortality is how well patients recognise the symptoms of an asthma attack. It has been suggested that individuals who under-recognise asthma symptoms (“poor perceivers”) and individuals who experience intense symptoms during relatively mild attacks (“over perceivers”) are at high risk of dying from asthma. However, presently there is no consensus as to what constitutes “normal” symptom perception in asthma. We have previously shown in 2 PSI supported studies that an acute increase in lung volume (hyperinflation) during an asthma attack is the most important mechanical contributor to breathlessness.
In the study, we hope to determine the normal range of respiratory symptoms during induced airway narrowing (bronchoconstriction) in asthma. We also wish to determine whether individuals with abnormal perception of bronchoconstriction have abnormal perception of hyperinflation. We will describe the characteristics of individuals with abnormal perception, and perform detailed studies of their sensory and mechanical responses to induced airway narrowing. Ultimately, this research will help define and clarify the cause and significance of abnormal symptom perception in asthma.
Dr. Philip A. Marsden, University of Toronto
Contribution of Lung-specific Alterations of Neuronal Nitric Oxide Synthase in the Pathogenesis of Asthma
Asthma is a chronic disease of the airway, in which stimuli, such as exercise, cold or environmental allergens can stimulate a persistent constriction/tightening of the airway, immediately reducing the capacity to breathe. While investigators have been examining the potential causes of this disease for years, few advances have been made beyond relief of the symptoms; a cure does not yet exist. Research has recently progressed to examine the contribution of specific genetic alterations to the pathology of asthma. Thus, the association of a specific genotype with the presentation of asthma, may lead to new and novel treatments. Recent evidence suggests that the biologically significant gaseous molecule, nitric oxide (NO), which is normally produced in our bodies, may play a role in the pathology of asthma. Further, the mutation of the gene for one of the enzymes which produces NO (nNOS) is associated with asthma. These investigations will examine the regulation and consequences of lung-specific alterations of this gene on the pathophysiology of asthma in humans, and in a mouse model of this disease. The results of these investigations may provide novel new therapeutic approaches to the treatment of this disease.
Dr. Martin Stämpfli, McMaster University, Hamilton
Impact of chronic allergen exposure on immune inflammatory processes in the airway
While allergens cause serious disease in certain individuals, they are on their own rather innocuous agents. In contrast to harmful pathogens such as viruses, bacteria and parasites, allergens do not replicate after inhalation and are unlikely to cause tissue damage. Consequently, there is no reason to mount immune inflammatory responses to eliminate these agents. That, in spite of universal exposure to aeroallergens, 85% of the population do not develop allergic diseases, may suggest that the immune system has evolved effective regulatory mechanisms that prevent the generation of immune inflammatory responses. In this proposal, we wish to investigate these regulatory principles. We hope that this knowledge will enable us to understand better why certain individuals develop allergic diseases. Ultimately, we wish to translate this knowledge to novel management and therapeutic treatment strategies.
Dr. Marie Faughnan, University of Toronto
Impact of Fine Particulate Pollution of Dynamic Hyperinflation in COPD
Population studies have shown morbidity from lung disease to increase with increasing ambient air pollution, particularly the fine particulate fraction. However, the mechanism remains unclear. One theory is that inhaled particles lead to inflammation in the lung, which in turn, leads to airways obstruction. Worsening airways obstruction, in people with chronic obstructive pulmonary disease (COPD) and therefore underlying chronic airway obstruction, would lead to worsening symptoms and sometimes frank respiratory failure and death. Considerable research is addressing the first part of this mechanism, the inflammatory process. However, evidence regarding the second part, the worsening of airways obstruction, is insufficient. This is likely due to the fact that most studies of air pollution on lung function have studied healthy subjects or those with mild asthma and have used simple lung function measures that are more likely insensitive to small changes.
We propose a pilot study to clarify the effect of fine pollution on airways obstruction by studying people with mild-moderate COPD and measuring a more sensitive outcome. This involves measurement of airway obstruction during exercise as well as its effect on pattern of breathing, specifically hyperinflation. We will use state-of-the-art technology to expose subjects in a controlled way, to fine particulate pollution, in one of the three laboratories in North America with the expertise and technology available. The results of this study will hopefully improve our understanding of the mechanism of respiratory health effects of air pollution.
Dr. Denis E. O’Donnell, Queen’s University, Kingston
Mechanisms of Dyspnea during Dynamic Lung Hyperinflation in COPD
In patients with chronic obstructive pulmonary disease (COPD), the ability to exhale air from the lungs is limited because of narrowing and collapse of the airways. When breathing increases, as for example during exercise, lung emptying with each breath is incomplete and air trapping occurs, sometimes to alarming levels. This over-distends the lung and chest and can contribute to breathing discomfort. We have developed a breathing circuit that can simulate the airway closure of COPD and allow us to examine the behavior of the muscles of breathing when the lung and chest are over-distended. We believe that breathing discomfort arises because lung over-distention uncouples the usually harmonious relationship between the powerful drive to breathe and the actual ability to breathe in. Several sub-studies are planned to test this working hypothesis.
Dr. Michael Tschakovsky, Queen’s University, Kingston
Limb Oxygen Delivery Adaptation to Exercise in COPD: Effects of Exercising Muscle Mass and Multi-modal Pulmonary Rehabilitation Program
People with chronic obstructive pulmonary disease (COPD) find it very difficult to exercise. This intolerance to exercise means that they are extremely inactive. Inactivity in this patient population results in alarming reductions in muscle mass and function, and eventually disability and social isolation. Therefore, a key intervention to manage health and function is exercise. However, designing interventions to make it easier for these people to exercise requires that we understand what contributes to their intolerance for exercise. Interestingly, these patients often identify fatigue in the exercising muscles as the reason they stop rather than breathlessness. Delivery of oxygen to muscles can influence how well muscles can exercise. In normal healthy people, substantially more oxygen can be delivered to a small exercising muscle mass than a large one. There is reason to believe that this effect might be even greater in COPD.
Since the focus of exercise rehabilitation programs is to maximize the improvements of muscle function and fitness, understanding the role of exercising muscle mass in determining oxygen delivery to exercising muscle will provide important insight to guide rehabilitation approaches. The proposed experiments will apply novel, non-invasive measurement of the dynamic response of blood flow to muscles during exercise to shed light on these questions.
Dr. Gerard Cox, McMaster University, Hamilton
Identification of Survival Factors in Neutrophils
Certain lung diseases – e.g. emphysema, chronic bronchitis – are caused by white blood cells enzymes damaging the lung or airway tissue. People who get these diseases for some reason get prolonged or excessive accumulation in the lungs, of neutrophils – a normal white blood cell that is essential for protecting against infection. Normally, these cells die and are cleared away without a trace as inflammation resolves. This study will examine how the survival of these is controlled. It is hoped that by understanding how cell survival is controlled we might discover new treatments that would kill off unnecessary cells and so limit the damage done to lung tissue.
Dr. Michael Fitzpatrick, Queen’s University, Kingston
Nasal Resistance and Oronasal Partitioning of Ventilation during Sleep in Obstructive Sleep Apnea
This proposal will examine how nasal obstruction influences nose versus mouth breathing during sleep in patients with mild obstructive apnea (OSA). The first project will measure nasal resistance in overnight inpatients with OSA and simultaneously measure how much of each breath is taken through the mouth and how much through the nose. In this way, it will be possible to find out whether nasal resistance changes during sleep and how/if this affects nose and mouth breathing in patients with OSA. This may be important because mouth-breathing appears to increase the tendency with OSA. The second project will measure the effect of a nasal decongestant on mouth breathing and sleep apnea severity in patients with OSA – it is anticipated that the nasal decongestant will reduce mouth breathing during sleep and therefore reduce sleep apnea severity.
Dr. Larry Wolfe, Queen’s University, Kingston
Respiratory Limitation to Exercise Tolerance in Late Gestation: Fact or Fiction?
Breathlessness (dyspnea) is a common complaint during pregnancy and is experienced by up to 70% of healthy pregnant women. To help determine that cause of dyspnea, we will study fifteen healthy pregnant women with dyspnea, fifteen healthy pregnant women without dyspnea, and fifteen healthy non-pregnant women. All subjects will undergo basic pulmonary function tests, a special test involving measurement of mechanical breathing factors and breathing sensations. Statistical methods will be used to determine the most important factors that predict the occurrence of dyspnea in pregnancy. The results will contribute to the formulation of guidelines for physical activity and work during pregnancy for women in occupations involving strenuous exertion (military service, police work, firefighting, athletic competition).
Dr. Zhou Xing, McMaster University, Hamilton
Modulation of Chemotherapy-weakened Innate Immunity in the Lung by Gene Transfer
Acute bacterial pneumonia is a common type of lower airway infection which has been a leading cause of death across the world. The Gram-negative (G-) bacterium accounts for the majority of cases that occur to hospitalized patients, particularly those who are on anti-cancer chemotherapy. The mortality of G-pnemonia has been around 50%. This is because this type of infection is often resistant to antibiotic treatment and there has not been an effective preventative vaccination program in place. Unfortunately, we have not completely understood the mechanisms of chemotherapy-weakened innate immunity. In this proposal, we have proposed studies to investigate the mechanisms of weakened host immune responses caused by anti-cancer agents in experimental models. We have also planned to apply our current knowledge to developing the molecular means to improve the innate immunity in such hosts.