The mortality burden of lung diseases is only exceeded by those of heart and blood vessel disease. Environmental stimuli, such as inhaled cigarette smoke, pollutants, or allergens, can produce an inflammatory response (an accumulation of white blood cells and tissue damaging proteins) in the lungs. While this response acts as a useful defense mechanism in most individuals, it can lead to structural tissue changes in the lungs and development of disease, in a susceptible person. The underlying hypothesis of our research is that environmental influences trigger an exaggerated inflammatory response in genetically susceptible individuals, with the resulting disease phenotypes of asthma, chronic bronchitis, airflow obstruction, and emphysema (COPD).

Dr. Peter Paré is the Director, the iCAPTURE Centre, and Professor, Department of Medicine. Dr. Paré and his colleagues, Drs. Bob Schellenberg and Chun Seow are actively investigating a scheme of events which relate bronchoconstricting stimuli to the ultimate airway narrowing that occurs. In vitro studies from their laboratory using tracheal smooth muscle from various mammalian species, including human, have shown that a decrease in the load impeding smooth muscle shortening can have a profound influence on the degree to which the airways will narrow. In ongoing work they are examining isotonic and isometric length-tension properties of smooth muscle in human peripheral airways using a specially designed myographs. Dr Paré has a major NIH grant to study Human Airway Remodeling in disease.

Dr. James Hogg is a Pathologist at St. Paul's Hospital in Vancouver and has been a Professor in the Faculty of Medicine at the University of British Columbia since 1977. Dr. Hogg's research is focused on studies of the inflammatory process in the lung with particular reference to the pathogenesis of peripheral airways obstruction in chronic obstructive lung disease and asthma. He is currently investigating the hypotheses that latent viral infections contribute to the changes in leukocyte kinetics that are relevant to the pathogenesis of emphysema and also carries out studies designed to develop a method of measuring emphysema using a combination of CT scanning and histology.

Dr. Tony Bai is an Internist and Respirologist at St. Paul's Hospital. The focus of DR Bai's research is investigation of determinants of asthma severity, and exploration of the role of interactions between the immune system and airway innervation in the expression of the inflammatory response in the lung.

Dr. Shizu Hayashi is an Associate Professor, Department of Pathology and Laboratory Medicine. Dr. Hayashi's research is focused on understanding how the adenovirus E1A protein regulates host genes in lung cells to increase the production of inflammatory mediators.

Dr. Richard Hegele is an Anatomical Pathologist at St. Paul's Hospital in Vancouver and an Associate Professor, Department of Pathology and Laboratory Medicine. Current research addresses the interaction of lung viral infections with allergens and pollutants, as pertains to the initial onset of asthma in children.

Dr. Andy Sandford is an Assistant Professor, Department of Medicine. The focus of Dr. Sandford's research is investigation of the genetic basis of obstructive lung disease. He collaborates with Dr. Paré to study susceptibility genes for chronic obstructive pulmonary disease and is studying two large cohorts of individuals. The first cohort (recruited by Drs. Moira Chan-Yeung from UBC and Allan Becker from the University of Manitoba) contains infants at high risk for developing allergic diseases and is being used to evaluate the importance of genetic risk factors for the development of these diseases. The second cohort (recruited as part of the NHLBI Lung Health Study) contains individuals whose lung function has been followed for five years. Genetic factors that affect the rate of decline of lung function are being investigated in this cohort. This work is a collaboration with Drs. John Connett from the University of Minnesota and Nicholas Anthonisen from the University of Manitoba.

Dr. Robert Schellenberg is an Internist and Allergist / Immunologist at St. Paul's Hospital in Vancouver and Professor and Head of the Division of Allergy and Clinical Immunology in the Department of Medicine, UBC. The focus of his research is on asthma and allergic inflammation with primary interests in the mechanisms of excessive airway narrowing of asthmatic tissues and the modulation of chemotaxis and apoptosis (programmed cell death) of basophils and eosinophils. His investigation of human airways has brought attention to the importance of changes in extracellular matrix elements as the cause of excessive smooth muscle shortening in asthma.

Dr. Chun Seow is an Associate Professor, Department of Pathology and Laboratory Medicine. The focus of his research is understanding the structure-function relationship in smooth muscles in general, airway smooth muscle in particular. Specifically he is studying changes in ultrastructure of contractile and cytoskeletal filaments and proteins in smooth muscle at different muscle lengths and under physiological/pathological conditions, and correlating these changes to mechanical functions of the cell. His other interests include skeletal muscle mechanics, ATPase cycle associated with the crossbridge cycle in muscle contraction, energetics of muscle contraction, and mathematical modeling of muscle contraction.

Dr. Stephan van Eeden is an Internist at St. Paul's Hospital and an Associate Professor, Department of Medicine. The focus of DR van Eeden's research efforts are mechanisms of lung inflammation, particularly lung inflammation caused by infection, cigarette smoking and air pollution. This research covers a broad range of clinical conditions such as pneumonia, chronic bronchitis and emphysema and acute respiratory distress syndrome. Current research addresses the response of the bone marrow during acute and chronic lung inflammation. He has shown that white cells released from the bone marrow play a crucial role in the lung inflammation elicited by cigarette smoke and particulate air pollution. This research has lead to the novel hypothesis that white cells released from the bone marrow are responsible for the increase heart and lung disease and deaths in subjects exposed to high levels of air pollution.

Dr. Del Dorscheid attends in the medical intensive care unit at St Paul's and is a researcher in the iCAPTURE Centre. As a young physician-scientist he leads an active research group investigating the role of the airway epithelium in the genesis of inflammatory airways diseases. Present projects include the role of glucocorticoid-induced airway epithelial cell apoptosis, novel glycoproteins involved in the repair of an injured epithelium, and the expression of FasL as an immune barrier for the airway in the changes associated with chronic airways remodeling.

Dr. David Walker is an Associate Professor, Department of Pathology and Laboratory Medicine. The focus of Dr. Walker's research has been the process of white blood cell migration in the lungs. In the course of this work he has identified and described a novel avenue for the trafficking of both molecules and white blood cells across the blood vessel walls of the lungs at tricellular corners in the endothelium. He has demonstrated a pathway from both capillaries of the alveoli and postcapillary venules of conducting airways to the respective airways along which white blood cells appear to migrate. This pathway is characterized by fibroblasts that singly in the alveolar walls and as a reticulum in the conducting airway walls provide a substrate along which white blood cells may crawl from holes in the vascular basal laminae to holes in the epithelial basal laminae. This is a completely novel observation and may transform how the process of leukocyte migration is both viewed and how it is mediated. He has developed experimental models for both neutrophilic and eosinophilic white blood cell migration that are relevant to pneumonias, cystic fibrosis, allergic inflammation and parasitic inflammatory responses.

These diseases are the basis for developmental problems, heart attacks, strokes, kidney failure, high blood pressure, leg amputations, and blindness. Atherosclerosis, commonly termed, "hardening of the arteries", is by far the leading cause of death worldwide (WHO). Atherosclerosis is a process in which blood vessels become narrowed and blocked. Injury of cells lining the blood vessels (endothelial cells) causes accumulation of fat, white blood cells, and muscle cells (plaque) in the vessel wall. Cigarette smoking, a fatty diet, lack of physical activity, obesity, and diabetes combine with family history to increase the risk for atherosclerosis, but the precise way this disease begins remains only partially defined. We will capitalize on the new imaging infrastructure to answer important questions about how this devastating disease process begins.

Dr. Bruce McManus is the Co-Director of the iCAPTURE Centre and a Professor, Department of Pathology and Laboratory Medicine. His research focuses on Transplant Vascular Disease (TVD), which is an accelerated form of atherosclerosis that occurs in transplanted organs, and is the main cause of death in heart transplant recipients after one year, with major implications for the now more than 50,000 heart transplant recipients (ISHLT Registry 1999). Because TVD occurs early and so rapidly, and because both environmental and genetic factors are at play, many insights from this disease can be applied to the broader atherosclerosis problem.

Dr. John Hill is a Research Scientist in the Healthy Heart Program at St. Paul's Hospital in Vancouver and an Assistant Professor, Department of Pathology and Laboratory Medicine. A specialist in cholesterol metabolism, Dr. Hill is the Director of the Atherosclerosis Specialty Lab (ASL) located within the Healthy Heart Program at St. Paul's Hospital. Dr. Hill's research is focused on the identification of specific relationships between the structural and functional properties of hepatic lipase and lipoprotein lipase so that their role in the metabolism of cholesterol and triglyceride and in the development of cardiovascular disease can be more clearly defined.

Dr. Issy Laher is an Associate Professor, Department of Pharmacology and Therapeutics. Dr. Laher's primary research interest is in the understanding the function of small blood vessels in health and disease by studying the mechanisms whereby blood vessel diameter is modified on both short and long term basis.

Dr. Casey van Breemen is a Professor, Department of Pharmacology and Therapeutics and Pathology and Laboratory Medicine. Dr. van Breemen's primary research interest is calcium signalling in smooth muscle and endothelial cells. In the past he has contributed to the understanding of calcium entry through the plasmalemma and calcium release from the endoplasmic reticulum. His recent work is focused on the mechanisms whereby both membrane systems generate intracellular calcium gradients and how these gradients increase the informational content of the calcium signal.

Heart failure occurs when the heart is no longer able to pump sufficient blood to meet the energy requirements of the body. Heart failure is an increasingly significant health problem, primarily because of our aging population. In the next century, the most common, most expensive, most debilitating, and most deadly disease will be heart failure. Heart failure is the end-stage result of a variety of insults and other diseases, including long-standing mechanical overload (such as high blood pressure), "hardening" of the arteries supplying blood to the heart, viral infections of the heart, infections elsewhere in the body, and other diseases (such as diabetes mellitus). At the current time, the exact mechanisms that lead to the development of heart failure are not known. What is known is that the heart undergoes profound phenotypic changes during heart failure progression: some myocytes (heart muscle cells) are lost or atrophy, while others change their size, shape, and orientation. In addition, extracellular matrix and vascular structures between individual myocytes change.

Dr. Bruce McManus is the CO-Director of the iCAPTURE Centre and a Professor, Department of Pathology and Laboratory Medicine. His research focuses on myocarditis, both infectious and non-infectious, which is a major cause of sudden unexpected death and heart failure in people less than 40 years of age. Using the murine - coxsackievirus B3 (CVB3) model, his current research focuses on the dynamic intracellular tension between host target cell survival and death. Viral life-promoting and death-inducing mechanisms largely determine target cell fate and the extent of virus proliferation and spread within an infected organ. In particular, viral proteases, which are integral to production of viral progeny, also cleave specific host cell proteins involved in maintenance of myocyte structural integrity, protein translation, cell survival and apoptosis. In response to such protease-induced damage and partly in support of virus replication, host survival mechanisms are activated within infected cells, sustaining myocyte viability and at times myocardial integrity. Meanwhile, death-inducing proteases of the infected cell itself are activated. A shift in the balance between life and death signaling and the extent of cardiomyocyte structural damage will have a major impact on the potential for progression to disadvantageous remodeling, dilated cardiomyopathy, and, ultimately, congestive heart failure.

Dr. Keith Walley is an Intensive Care Physician at St. Paul's Hospital and a Professor, Department of Medicine. The focus of Dr. Walley's research is to investigate the mechanism of decreased left ventricular contractility during sepsis and to investigate impaired oxygen extraction by peripheral tissues during sepsis. Left ventricular contractility has been measured using sophisticated left ventricular pressure volume relationships in acute animal model experiments. Isolated cardiac myocytes are studied in tissue culture. Dr. Walley maintains a strong collaboration with Dr. James A. Russell who is active in many of the recent clinical trials in ARDS and sepsis.

Coxsackieviruses are being studied by Dr. Yang and Dr. McManus. The focus is on linking the genotype of both host and virus to the phenotype of infection (i.e., which organ is affected), and particular attention is paid to host cell signaling and cell death pathways. While these viruses infect heart muscle, and are directly pertinent to heart failure, the important advances engendered by the iCAPTURE infrastructure will also be applicable to our understanding of gene-to-phenotype linking in other viral disorders. The mechanisms of tropism (a virus's ability to infect different tissues) and persistence will also be elucidated by Dr. Hogg, Dr. Hayashi and Dr. Hegele. These investigators study viruses that infect cells lining the lung, and contribute to the inflammation underlying emphysema and asthma (i.e. adenovirus, respiratory syncytial virus).

Intracellular calcium is now recognized to be critically important in the initiation and progression of normal and abnormal cellular events in all tissues. Dr. van Breemen has devoted his career to the study of calcium regulation, and working with Dr. Laher, Dr. Seow, and Dr. McManus, he is continuing the study of calcium and other signaling molecules (such as nitric oxide) in endothelial and smooth muscle cells of the vessels, as well as in cardiac myocytes. The balance between pro-life and pro-death signaling in lung, heart, and blood vessel cells is under intense study by Drs. McManus, Walley and Pare, and UBC collaborators Drs. Karsan, Steinbrecher, Moore, and Fedida.

The biology of white blood cell (leukocyte) migration to sites of injury is a fundamental issue with relevance to heart, lung, and blood vessel disease. The interaction of activated leukocytes with blood vessel endothelium, interstitial cells, and epithelial cells is under intense study by a number of investigators including Dr. David Walker, Dr. Van Eeden, Dr. Walley, and Dr. Hogg.

These proteins are involved in many pathological processes, and are being studied by iCAPTURE scientists in the following contexts: the creation of new blood vessels, airway hyperresponsiveness (Dr. Schellenberg, Dr. Bai, and Dr. Paré), atherogenesis (Dr. van Breemen, Dr. Hogg, and Dr. McManus), vascular-myocardial coupling in sepsis (Dr. Walley), and virus-induced heart disease and post-transplant rejection (Dr. Laher, Dr. McManus, Dr. van Breemen).

Lipids are critically involved in atherogenesis. Drs McManus, Laher, and Hill are pursuing the role of oxidation of fats in atherogenesis, in collaboration with Drs. Steinbrecher and Moore. Dr. Hayden has pursued the role of lipoprotein lipase, and more recently, the ABC1 protein, in atherogenesis, bringing his genetic expertise and discoveries to collaborative partnership with Dr. McManus.

The recent advances in CT and MRI have revolutionized the diagnosis and assessment of human disease processes. However, despite the enormous quantitative potential of these digital imaging techniques, diagnosis still largely relies on subjective interpretation of pictures. The next wave of progress in the imaging field will be the development of models for quantitative analysis of image data. Drs. Mayo and Muller, working with Dr. Harvey Coxson, Dr. Paré, and Dr. Hogg, have been at the forefront of this field. The establishment of the requested infrastructure will permit investigators to capitalize on their expertise, and develop innovative models to analyze structure-function relationships in pulmonary diseases, as well as extending the methods to the cardiovascular system.