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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 2003-2004 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.
Dr. James Lewis, St. Joseph’s Healthcare, London
The role of SP-A in modulating host defence
Our research has evaluated the role of the surfactant system (the inner layer of the lung) in the cause and progression of acute lung injury. To date, most of this work has focused on ‘rescuing’ lung function in critically ill patients by instilling exogenous surfactant into the injured lung, since the major function of surfactant is to maintain lung stability. Results of these clinical studies have been disappointing however, most likely because these patients were too sick at the time of treatment. We have now decided to look at a recent discovery that a specific surfactant protein called SP-A, has another important function, which is to decrease the inflammation that occurs within the lung during the development of lung injury. Since this inflammation can ‘spillover’ into the circulation and damage other organs thereby contributing to the death of these patients, determining the exact role of this protein in the inflammatory process is important. To address this issue, we will use a well-known model of lung injury in mice, and a unique and recently developed (only the second in the world) method to measure inflammation coming from the lung into the circulation (isolated perfused lung). Mice genetically deficient or with excess amounts of SP-A will be studied to see if this protein protects against inflammation. These studies will ultimately lead to more effective treatments for patients with lung injury.
Dr. Sanjay Mehta, University of Western Ontario, London
Mechanisms of septic pulmonary microvascular endothelial cell barrier dysfunction
In critically ill patients, inflammation of the lung is a common clinical problem causing significant illness and with a high (~40%) 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 that NO from different cells has disparate effects on lung inflammation and lung injury. This has important implications for better therapy for lung injury targeted at individual cell types, associated with fewer adverse effects. Thus, our research using mice and isolated cells in cell culture aims to (1) gain a better knowledge of the mechanisms and factors causing lung inflammation, (2) understand how the body normally defends itself against lung injury and inflammation, and how this might be disturbed in the presence of disease, and (3) evaluate new medical therapies in lung inflammation.
Dr. Rudolf Veldhuizen, University of Western Ontario, London
The role of tissue inhibitor of metalloproteinases-3 in acute lung injury
Acute lung injury (ALI) is a disease characterized by severe lung dysfunction, occurs in people of all ages and has a mortality rate of approximately 30%. Causes of ALI include near drowning, smoke inhalation and infection. The objective of our research is to elucidate how ALI develops and, based on the knowledge obtained, how it can be treated. To study this, we have developed animal models of ALI that reflect this disease in humans. In this application we propose to use these animal models of ALI to specifically investigate proteins, such as tissue degradative enzymes, which may cause damage to lung tissue. These proteins are normally involved in tissue growth and repair but in situations like ALI, these proteins may become damaging to the lung. Ultimately this research may help in designing new treatment strategies to improve the outcome in patients with this disease.
Dr. Zhou Xing, McMaster University, Hamilton
Mechanisms and modulation of chemotherapy-weakened innate immunity in the lung by using gene-based immunotherapeutics
Acute bacterial pneumonia is a common type of lower airway infections which has been a leading cause of death across the world. The Gram-negative (G-) bacterium accounts for the majority of cases that occur in hospitalized patients, particularly those who are on anti-cancer chemotherapy. The mortality of G-pneumonia has been around 50%. This is because this type of infection is often resistant to antibiotic treatment and there has not been an effective preventive vaccination program in place. Enhanced understanding of the mechanisms of chemotherapy-weakened innate immunity, is much needed. 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 will also apply our current knowledge to developing gene-based immunotherapeutics to improve the innate immunity in such hosts.
Dr. Haibo Zhang, St. Michael’s Hospital, Toronto
Molecular and cellular mechanisms of human neutrophil peptides in lung injury
In many humans lung diseases, such as bacterial pneumonia and acute respiratory distress syndrome (one of the most severe fatal lung diseases), vast numbers of a particular type of white blood cell, neutrophils, migrate into the lungs. Neutrophils are essential to fighting off infection in several ways, including by secreting toxic substances, such as human neutrophil peptides (HNP). Although at normal concentrations HNP can kill bacteria in the lung, our research suggests that high concentrations of HNP actually induce lung injury. The proposed study will further this work. We will search for cell surface receptors that imitate the action of HNP in human lung cells. We will use established human lung cell lines and blood mononuclear cells to examine our hypothesis that HNP initiate their biological effects through surface receptors in lung cells. Once the receptor (s) is/are cloned, the role of HNP in lung diseases can be more clearly define. Our study will provide potential clinical applications that may lead to new treatment strategies of inflammatory lung diseases.
Dr. Jack Gauldie, McMaster University, Hamilton
Airway remodeling in a murine model of asthma: epithelial and mesenchymal interactions in the airway
The prevalence, hospitalizations and deaths from asthma have been steadily increasing in Canada, as well as worldwide, since the 1980’s. It is the most common chronic respiratory disease in childhood, affecting approximately 10% of children, and is the cause of approximately 20 deaths in children and 500 deaths in adults per year in Canada. Many of the symptoms of asthma relate to the increased ‘twitchiness’ of the airways, or ‘airway hyperresponsiveness’ (AHR), which results in narrowing of the airways and breathlessness. The underlying cause of this AHR is not yet understood, but is thought to be related to certain structural changes that occur in the airway, which include fibrosis and increased muscle mass. In this study, we used a mouse model which shows similar structural changes in the lungs as well as increased AHR. The use of such a model allows us to examine the changes in the airway during the onset and establishment of AHR and airway structural changes. Various proteins are thought to be important in the development of the airway structural change, and may be produced by the cells of the airway. If we are able to measure the production of these proteins at various times in the development of airway structural changes, we could gain insight into the causes of these changes, and, hopefully, into the cause of AHR. Using recently developed equipment, termed a ‘laser capture microdissection microscope,’ we are able to dissect out distinct cell populations from the mouse lung at different stages of development of the disease and measure the potential that each cell type has for producing these factors. In this way we have the ability to determine which cells and secreted proteins are important in the development of chronic structural changes, allowing us to develop treatments targeted at these in the future.
Dr. Mark Inman, McMaster University, Hamilton
The role of IL-13 and TH2 mediators in sustained allergen-induced airway hyperresponsiveness
We believe that airway hyperresponsiveness (a tendency of airways in the lungs of people with asthma to narrow more readily than in healthy individuals) is a major contributor to the burden of disease in asthma. The cause of airway hyperresponsiveness is not known, but possible contributors include inflammation and chemical release in the lung, as well as scarring of the airway walls in the lung. In these studies, we will study these two possible causes using mice, which have been manipulated so that they develop an allergic response in their lungs that is similar to asthma. We expect to find that in order to prevent the scarring component of airway hyperresponsiveness, treatment to prevent the inflammation and chemical release in the lungs must be initiated very early in the course of the disease.
Dr. Luke Janssen, McMaster University, Hamilton
Regulation of Rho, ROCK and myosin light chain phosphates by leukotrienes and ß-agonists
Asthma is characterized by narrowing of the airways and hyperresponsiveness to many contracting agents. Leukotrienes are a group of molecules believed to be instrumental in many of these changes. Another group of molecules, the ß-adrenergic agonists (found in asthma “puffers”) are widely used to control these changes. However, there is much that we do not know regarding how leukotrienes and ß-agonists work. There is growing interest in a signaling pathway which involves 3 key enzymes called Rho, Rho-activated kinase (ROCK) and myosin light chain phosphates (MLCP). The effects of leukotrienes and ß-agonists on these three enzymes in the lungs are essentially unexplored. We now propose to look specifically at these questions using biochemical techniques which we have already used successfully in other research questions. In particular, these enzymes will be purified from human lung tissues, then studied under controlled conditions to examine whether/how leukotrienes and ß-agonists affect the activities of Rho, ROCK and MLCP. At the same time, we will demonstrate that these biochemical changes result in the expected mechanical changes.
Dr. Roger Goldstein, University of Toronto
Individualized pulmonary rehabilitation (PR) after acute exacerbation (AE) of chronic obstructive pulmonary disease (COPD)
In a recent study about life after pulmonary rehabilitation, we found that individuals reported flare-ups as a main reason for not keeping up their exercises. A short-term period of rehabilitation may prove to have an important impact on regaining their strength and improving their overall health. This study will look at the effects of an individualized short period of rehabilitation on quality of life and exercise tolerance in individuals with COPD after they have a flare up of their symptoms. We will ask individuals who have completed pulmonary rehabilitation to participate. If they agree, they will be assigned to a treatment or a control group. When they have a moderate or sever flare up, they will be re-tested, and those in the treatment group will have a 2-week period of rehabilitation that will focus on improving their exercise tolerance, and their ability to manage their illness. We will compare the two groups.
Dr. Steve Iscoe, Queen’s University, Kingston
Respiratory muscle fatigue during dynamic hyperinflation
People with chronic obstructive lung diseases are subject to acute episodes in which breathing becomes extremely difficult; unless treated, the consequences can be fatal. During these episodes, the person is forced to breathe at an increased lung volume, something that makes inspiration even more difficult. In part, this may be because the adaptations of the inspiratory muscles, especially the diaphragm, to the chronic disease may make these muscles less well able to handle the acute worsening of their condition. Aside from the worsening of oxygen and carbon dioxide levels in the blood accompanying the impaired ventilation, the stress on the respiratory muscles may cause injury to them. In a small animal model of these acute exacerbations of the disease, I will determine if the muscles are indeed injured by detecting the release of a particular protein from them into the blood. I will identify which muscles are the source of this protein by seeing which muscle cells have damaged membranes and, as a consequence, take up a special dye. These results will provide new information about how these acute, and dangerous, episodes of difficult breathing affect the respiratory muscles.
Dr. Denis O’Donnell, Queen’s University, Kingston
The effects of combined COPD and obesity on ventilatory mechanics, dyspnea and exercise tolerance
Obesity and chronic obstructive pulmonary disease (COPD) are both common health problems in Canada. Obesity in COPD may have serious adverse affects on the degree of breathlessness and inability to exercise. Specifically, we will study the additional effects of obesity on abnormalities in lung function, respiratory muscle function and ventilatory responses to exercise already experienced in patients with COPD.
Dr. Michael Fitzpatrick, Queen’s University, Kingston
The effect of continuous positive airway pressure on nasal resistance in patients with obstructive sleep apnea
Continuous positive airway pressure (CPAP) is the most commonly used treatment for Obstructive Sleep Apnea (OSA). Patients with OSA often complain of a blocked or runny nose when using CPAP and these nasal symptoms often result in the patient abandoning the treatment. There is no objective information available on the effect of CPAP on the nasal airway. This project will examine the effect of CPAP on the resistance of the nose, and how added humidification affects the change in nasal resistance when CPAP is applied. A cold air challenge will be used to categorize patients into those with nasal hyperreactivity and those with normal nasal reactivity, so that it will be possible to compare the nasal response in each group. It is hoped that improved understanding of the effects of CPAP on the nose will ultimately lead to more comfortable CPAP treatment for the patient and therefore improved CPAP compliance.
Dr. Chung-Wai Chow, University of Toronto
Regulation of syk-mediated signal transduction in inflammatory cells
The lung performs a key immune function by removing inhaled pollutants and microorganisms before they can cause harm. This is primarily done by immune cells such as macrophages and mast cells which normally reside in the lung and by circulating cells such neutrophils and lymphocytes. They ingest inhaled foreign particles and release cytotoxic mediators to destroy microorganisms. Syk is a molecule that is present in all immune cells and plays a pivotal role in normal immune response. It regulates many aspects of immune function including the ingestion of foreign particles and release of cytotoxic mediators. When activation of the immune response is not counterbalanced by negative regulatory signals, the cytotoxic mediators can cause tissue injury. Lung diseases where inflammatory tissue injury is a primary event include asthma, interstitial pneumonitis, pulmonary fibrosis and pneumonia.
Much is known about the structure and the mechanism that activate Syk. However, little is known about those that negatively regulate Syk activity. The purpose of this proposal is to identify the mechanisms that will not only contribute significant knowledge to the basic mechanisms of immune regulation but will potentially identify pathways that can be targetted when designing drugs for the treatment of immune-mediated lung diseases such as asthma and interstitial pneumonitis.
Dr. Manel Jordana, McMaster University, Hamilton
Immune inflammatory and reparative responses to continuous exposure to house dust mite 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 this 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 human 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 sustained 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.
Dr. Larry Wolfe, Queen’s University, Kingston
Phasic menstrual cycle effects on acid-base regulation and respiratory chemoreflex sensitivity
The human menstrual cycle involves alterations in blood progesterone and estrogen levels. Progesterone, which is high during the luteal phase and low in the follicular phase, has been shown to cause increases in breathing and reductions in the acidity of blood in humans. However the causes of progesterone-induced changes in breathing and acidity are poorly understood. To help determine the causes of breathing and acid-base balance changes that occur during the menstrual cycle, we will study 15 normal, healthy women during the luteal and follicular phases of the menstrual cycle. All subjects will undergo special tests to measure breathing sensitivity, and a two-stage exercise test involving measurement of blood acidity and the factors that determine acidity. Statistical methods will be used to identify the breathing and acid-base balance changes during the menstrual cycle, and to clarify the causes of these changes.