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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 2004-2005 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. Robert P Jankov
Reactive Nitrogen Species as Mediators of Pulmonary Hypertension in a Newborn Rat Model of Bronchopulmonary Dysplasia
Broncholpulmonary dysplasia (BPD) is a chronic lung injury, which primarily affects prematurely born infants. BPD was first described in the 1960s, following the introduction of mechanical ventilation for newborns, which allowed the survival of infants who would otherwise have died. In the past decade, there has been an overall increase in the incidence of BPD, owing to the dramatically increased survival of extremely premature infants born from 23 to 28 weeks’ gestation. Between half and two-thirds of this group may be expected to develop BPD, making it the most common chronic lung disease of infancy and early childhood. This is creating a growing pool of children who will potentially carry their impaired lung function with them into adulthood. In spite of the major impact that BPD poses, no effective preventative therapies have yet been developed. The development of sustained pulmonary hypertension in more severe cases of BPD is recognized as a major risk factor for death and morbidity. Therefore, interventions targeted at preventing pulmonary hypertension are likely to reduce BPD-related mortality and mortality in newborn infants. My work has focused upon the role of free radicals, and their products, upon the development of BPD and pulmonary hypertension. Through targeted interventional studies in newborn animals, I plan to better understand the roles of free radicals in lung injury with the goal of developing new therapies for premature newborns at risk of BPD.
Dr. Mingyao Liu
Pentraxin 3: A New Inflammatory Mediator In Acute Lung Injury
Acute respiratory distress syndrome (ARDS) is 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 morality. 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. We will also use animal models to determine the role of PTX3 produced by lung epithelial cells in acute lung injury. 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 defence in the lung. This novel concept may change the strategies for treatment of ARDS and acute lung injury.
Dr. Sanjay Mehta
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. Lorraine Tremblay
Modulation of the Inflammatory and Immune Response by Mechanical Ventilation
Mechanical ventilation is an important life saving supportive therapy used in a variety of circumstances from severe traumatic lung injury to exacerbations of chronic lung disease. Although basic research over the past few decades increased our understanding of how to use this technology, and a recent large multi-center trial has shown that how we mechanically ventilate patients with lung failure can have a significant effect on whether or not they survive, we still do no completely understand what is the optimal way to mechanically ventilate lungs in different diseases, nor do we fully understand the mechanisms by which different ways of ventilating the lung can lead to lung injury, complications, or death. One of the most common and most serious complications of mechanical ventilation is pneumonia. In our study we explore how mechanical ventilation affects the body’s ability to fight infections and whether we can reduce the chance of infection by changing how we mechanically ventilate the lungs. We hope that the information we will gain on how mechanical ventilation interacts with the body’s inflammatory and immune response will ultimately lead to fewer complications, and improved survival of patients needing respiratory support.
Dr. Haibo Zhang
Targeting ICAM/1LFA-1 Interaction for Controlling LPS-induced Lung Parenchymal-immune Cell Crosstalk
Endotoxin is a major cause of many human lung diseases, such as bacterial pneumonia, and acute respiratory distress syndrome (one of the most severe fatal lung disease that is frequently associated with sepsis). However, many expensive clinical trials using anti-endotoxin antibodies failed to treat these patients but the reasons remain unclear. We recently demonstrated that lungs cells can memorize endotoxin signal by making a molecule called intercellular adhesion molecule-1 (ICAM-1) that stimulate white blood cells to induce lung inflammation and lead to lung injury, even after endotoxin has been removed. This may provide a viable explanation for the failure of the clinical trials. The present research proposal will study further to examine how ICAM-1 can activate white blood cells. We will separately investigate the different portions of the structure of ICAM-1 to activate white blood cells. We will use current cell and molecular techniques to block the activation at cell level and in mouse models of human lung diseases. Our study will provide potential clinical applications that may lead to new treatment strategies of inflammatory lung disease.
Dr. Luke J. Janssen
Regulation of Rho and ROCK in Airway Smooth Muscle by Second Messengers
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 signalling pathway which involves 3 key enzymes called Rho, Rho-activated kinase (ROCK) and myosin light chain phosphatase (MLCP). The effects of 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 muscle tissues, then studied under controlled conditions to examine whether/how neurotransmitters and ß-agonists affect the activities of Rho, ROCK and MLCP. At the same time, we will directly measure contractions and relaxations in isolated tissues in order to demonstrate that these biochemical changes result in the unexpected mechanical changes.
Dr. Manel Jordana
Immune Inflammatory and Reparative Responses to Continuous Exposure to House Dust Mites 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 (thorough 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.
Dr. Parameswaran Nair
Regulation of Human Airway Smooth Muscle Cytokine Synthesis by Cysteinyl Leukortrienes
The two important components of asthma are inflammation of the airways and narrowing of the airways caused by shortening of the muscles lining them. Leukotrienes are a group of chemicals which are very powerful in causing shortening of the muscles. We now know that muscle cells do more in asthma than just shorten. They are able to make inflammation worse. This is probably one of the mechanisms by which asthma can get worse. It is not known whether leukotrienes, in addition to causing shortening of the muscles, can also cause muscles to produce inflammatory substances. A number of drugs are now available which can decrease the effects of leukotrienes. In this study, we will investigate whether leukotrienes and the drugs that decrease their effects can decrease the ability of muscle cells in the airway from producing inflammatory substances. We will also study the mechanisms by which they do that. We will be studying this using muscle cells that we will obtain from patients who have lung surgery at St. Joseph’s Hospital in Hamilton. The results of this study will help us to better use the drugs to decrease the effects of leukotrienes to prevent the chronic changes and scarring associated with long-standing asthma.
Dr. Martin R. Stämpfli
Impact of Mainstream Cigarette Smoke Exposure on Immune-inflammatory Responses Elicited by Clinically-relevant Allergens
It is widely accepted that environmental tobacco smoke, also known as ‘secondhand’ or ‘passive’ smoke, is a strong risk factor for the development of asthma. The impact of active smoking on the development asthma, however, is very controversial. The objective of the proposal is to investigate the impact of cigarette smoking on immune-inflammatory processes associated with asthma in mice. In our studies, we will investigate how cigarette smoke impacts inflammation elicited by allergens. We will also examine how this impacts lung structure and function. We believe that the proposed studies will further our understanding of the impact of cigarette smoke on immune-inflammatory processes and provide novel insight into the pathogenesis of asthma.
Dr. Roger Goldstein
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 period of rehabilitation may 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 to participate, they will be asked to call-in when they have a moderate or severe flare up. They will then be re-tested and assigned to a treatment or a control group. Those in the treatment group will have a 3-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.
It has been estimated that 1.5 million Canadians have COPD. The Lung Association is committed to reducing the burden of COPD in Canada. Non-pharmacological management of COPD by respiratory rehabilitation is effective in improving quality of life. The benefits diminish with time mainly because of non-adherence with the exercise program. Patients with COPD have identified acute exacerbations as the most important cause of program non-adherence. This project will enable clinicians to identify whether an abbreviated rehabilitation program after a COPD exacerbation will enable patients to regain their functional activity level and quality of life. It will provide important information for a future multicentre multidisciplinary RCT of abbreviated rehabilitation following acute exacerbations. If the intervention is effective, health care providers will be able to refer to COPD patients who have completed rehabilitation for an abbreviated PR program to improve their health-related quality of life and exercise tolerance. Such an intervention will reduce the impact of exacerbations on COPD morbidity.
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 or reverse them.
Dr. Michael Fitzpatrick
Physiology of Continuous Positive Airway Pressure (CPAP) Treatment in Obstructive Sleep Apnea
Continuous Positive Airway Pressure (CPAP) is the usual treatment for obstructive sleep apnea. Nasal symptoms are one of the biggest reasons that patients have difficulty tolerating CPAP treatment. Perhaps surprisingly, there has been no systematic evaluation to date of the effect of CPCP on nasal resistance. Recently, I have found no effect of CPAP given for one single six-hour exposure, on nasal resistance. This study is designed to examine the effect of repeated CPAP exposure during the first two months of CPAP treatment on the resistance of the nose, in patients with obstructive sleep apnea. Changes in nasal resistance could greatly alter the transmitted CPAP pressure, and thus significantly alert the therapeutic CPAP pressure requirement. The present study will examine objectively the transmitted CPAP pressure from CPAP pressure mask to chest, on the first night of treatment and again after 2 months of CPAP treatment. This will be the most definitive study to date examining the physiological interaction between CPAP treatment and the nasal and upper airway response to CPAP, both acutely and after 2 months of repeated CPAP use.
Dr. Margaret S. Herridge
One-year Outcomes in Survivors of the Severe Acute Respiratory Syndrome (SARS)
Virtually nothing is known about the long-term pulmonary function, exercise capability and quality of life in survivors of the severe acute respiratory syndrome (SARS). It is not clear whether these patients have any persistent physical morbidity. If they do, it is essential to understand whether this is on a pulmonary or an extrapulmonary basis and to identify the specific determinants and modifiers of disability.
The SARS outcomes study will represent the first comprehensive evaluation of the long-term morbidity of SARS. Patients will be followed at regular intervals after hospital discharge and lung function, ability to exercise and health-related quality of life over the 1-year follow-up and may provide insights into the type and timing of specific therapeutic interventions to minimize this morbidity. The morbidity period will be measured. These data will provide timely information about the nature and degree of disability associated with SARS.
Dr. Sherri Katz
Prevalence of Nocturnal Hypoventilation and Impact of Non-invasive Ventilation on Children and Adolescents with Satic or Progressive Neuromuscular Conditions
Breathing problems are a known and frequently fatal complication of neuromuscular disease, which first present at night. Treatment of this problem with night-time 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 include:
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. Larry Wolfe
Effects of Menopause on Acid-base Regulation and Respiratory Chemoreflex Sensitivity
The human menopause involves decrease in blood estrogen and progesterone that can cause changes in breathing and acidity of blood. Recent research has identified blood acidity as an important factor that can lead to bone loss. However, effects of blood acidity as a result of changes in estrogen and progesterone have not been studied during human menopause. To examine the changes in breathing, blood acidity and bone health during the menopause, we will study 30 postmenopausal and 30 premenopausal healthy women. All subjects will undergo special tests to measure breathing sensitivity and bone health, and an exercise test involving measurement of blood acidity. Statistical methods will be used to identity associations between changes in reproductive hormones, changes in breathing and blood acidity, and changes in bone health after menopause. This study will provide new information on the changes in breathing and blood acidity during menopause and their effects on bone health. The findings will also contribute to the development of health management approaches to prevent bone loss following menopause.