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Paul D. Blanc, M.D. Professor Medicine; Division Chief, Occupational Medicine Research Interests: Epidemiology of occupational lung disease, Asthma outcomes and Occupational toxicology Summary: Dr. Blanc's research program focuses on the epidemiology and toxicology of the pulmonary system. The research is comprised of two principal components: first, the longitudinal study of adults with asthma, examining outcomes of disease with emphasis on interactions between workplace exposures and disease severity and second, epidemiologic, population-based and controlled human exposure studies of acute chemical exposure effects. The research has been supported by a Research Career Development Award from the National heart Lung and Blood Institute and independent research grants from the NIH, CDC, American Lung Association, and the UC Tobacco-Related Diseases research Program.

Homer A. Boushey , M.D. Professor of Medicine; Division Chief, Allergy & Immunology Research Interests: Bronchial hyperreactivity in asthma. Effects of viral infection on airway function. Regulation of airway mucous secretion and vascular permeability. Summary: Dr. Boushey received his M.D. degree from the UCSF in 1968. He completed residency training in Internal Medicine at UCSF and at the Beth-Israel Hospital of Harvard Medical School. He then pursued specialty training in Pulmonary Medicine at Oxford University and at UCSF. He joined the UCSF faculty in 1974 and, except for a year's sabbatical at the University of Paris (Cochin Hospital), has remained here for his entire career. He has served as Vice-Chair of the Department of Medicine and Chief of the Medical Service (1989-1995) and recently as Chief of the Division of Allergy/Immunology and Director of the Asthma Clinical Research Center. Dr. Boushey's major academic interests include clinical research on the pathogenesis and treatment of asthma, focusing especially on the role of viral respiratory infections in triggering asthma exacerbations. Asthma has come to be regarded as a chronic inflammatory disease of the airways, but the causes, nature, and consequences of inflammation are imprecisely understood. Working closely with Drs. Fahy (Pulmonary), Avila (Allergy), Lazarus (Pulmonary), and Janson (Pulmonary, School of Nursing), Dr. Boushey's research team has focused on methods for assessing airway mucosal inflammation (eg., sputum induction), on examining the effects of new, specifically targeted therapies (egs., monoclonal anti-IgE antibody, cell adhesion molecular inhibitors), on comparing existing therapies (inhaled corticosteroids, long-acting beta-agonists, and leukotriene antagonists, given alone or in combination), and on defining the mechanisms by which viral respiratory infection alters upper and lower airway function. Asthma occurs uniquely in humans, and while animal models offer great promise for defining key steps in the pathophysiologic cascade that accounts for the structural and functional changes in asthma, confirmation of the relevance and importance of new findings ultimately requires testing in humans with the disease. Conversely, new targets for study through the application of genetic manipulation in murine models sometimes are defined by observations made in human subjects. The exchange of information between bench and clinical investigators is facilitated by the development and application of tests based on advances in molecular biology and genetics to the study of people. The era of truly "translational" research is opening, and will open first to centers where basic and clinical investigation is closely integrated, and where basic and clinical investigators have a tradition of exchange. Dr. Boushey regards these traditions at UCSF as essential for his own success in clinical research, and believes they also serve for the training of future academic investigators.

V. Courtney Broaddus, M.D. Professor of Medicine Research Interests: Role of apoptosis in asbestos-induced malignancy. Molecular interaction of asbestos fibers with mesothelial cells, specifically with regard to the role of cell surface adhesion receptors. Summary: Apoptosis is a highly regulated process of cell death, allowing the deletion of cells that are damaged or otherwise targeted for destruction. Resistance to apoptosis underlies both the development and the survival of tumors. Understanding the sites of resistance in tumors may lead to more effective therapy. Two signaling pathways are known to activate the proteases called caspases that mediate apoptosis: one, the DNA damage pathway which involves a mitochondrial step in order to activate caspases and the other the death ligand pathway which can bypass mitochondria to activate caspases directly. Crosstalk between the pathways may lead to synergistic apoptotic responses. We study apoptosis in mesothelioma and lung cancer lines, as models for highly resistant solid tumors. A major focus of the laboratory is 1) to identify mechanisms of resistance to apoptosis in these lines and 2) to identify means of amplifying apoptosis. We have now described a synergistic apoptotic response of mesothelioma lines when exposed to both a death ligand, TNF-related apoptosis inducing ligand (TRAIL), and chemotherapeutic agents. The synergy can be shown to involve amplification of mitochondrial depolarization and amplified release of cytochrome c. We are now studying the signaling steps by which these two pathways (death receptor and DNA damage) converge on the mitochondria andamplify apoptotic death. Other synergistic combinations appear to act at different levels within the cell, e.g. by increasing expression of the death receptors. Some examples of interest are the use of TRAIL or fas ligand together with proteasome inhibitors, with NFkappa B inhibition, and with triptolide, an inhibitor of cell arrest. In parallel in vivo studies, we are exploring synergistic effects in a nude mouse model of mesothelioma. In other work, we are starting microarray analysis of the response of mesothelial cells to toxic entities, such as asbestos fibers. In this approach, now called toxicogenomics, microarray studies of global cell responses to toxic agents may identify patterns of responses associated with toxicity. The analysis can highlight previously unrecognized toxic interactions with cells, allowing new hypotheses to be developed and explored.

James K. Brown, M.D. Associate Professor of Medicine Research Interests: Protease signaling Summary: Tryptase is the most abundant protein released from mast cells, which are inflammatory cells found in large numbers in the airways and lungs of patients with respiratory diseases such as asthma and pulmonary fibrosis. When released from mast cells, tryptase has the capacity to stimulate growth in nearby cells. Therefore, it may contribute to thickening of the airway wall in asthma, leading to increased airflow obstruction, and to scar formation in the lungs in pulmonary fibrosis, leading to worsening shortness of breath. Our research seeks to understand the mechanisms through which tryptase stimulates cells to grow so that improved pharmaceutical approaches can be developed to inhibit its growth stimulatory effects and can be employed as possible therapeutic agents in patients with asthma and pulmonary fibrotic disorders.

George H. Caughey, M.D. Professor of Medicine; Chief, Pulmonary & Critical Care Medicine Section, VAMC Research Interests: Regulation of lung and airway function by mast cell, leukocyte and epithelial proteases Summary: The laboratory's main goal is to understand the roles of enzymes released into the lungs and breathing tubes by mast cells and related white blood cells. Our studies suggest that these enzymes-specifically, tryptases and chymases, which alter the properties of selected target proteins by disrupting links in chains of amino acids-may be important in asthma, bronchitis, lung infections and diseases characterized by lung shrinkage and excessive scarring. The laboratory is also interested in a related enzyme, prostasin, which may regulate airway water content in cystic fibrosis, and in several enzymes that may promote airway scarring and recurrence of breathing problems in recipients of transplanted lungs.

Harold A. Chapman, M.D. Professor of Medicine; Chief, Division of Pulmonary and Critical Care Medicine Research Interests: Antigen presentation by MHC class II molecules important to immunity and autoimmunity and extracellular matrix remodeling important to cell migration and tissue repair Summary: Integrins are a well known family of cell surface adhesion protein receptors. Integrins attach to the matrix surrounding cells, and also to neighboring cells, and then convey information to the cell allowing it to respond. For example, cells suddenly devoid of their integrin attachments to their surrounding matrix frequently undergo a cell death program. Integrin function therefore affects cellular differentiation state, survival, growth, and movement. My lab has been studying a set of integrins widely expressed on epithelial cells and attempting to understand how the information conveyed by these integrins is regulated and whether there are critical pathways of signaling initiated through integrins that are needed for tumor progression and wound healing. The lab is primarily focused on the lung and hence our experimental models are mainly intended to model pulmonary fibrosis (scarring) and lung cancer. The main objectives of our current studies related to integrins are to understand integrin function in the context of epithelial cell trans-differentiation to fibroblast-like cells during lung repair (wound healing) and in the context transformed epithelial cell (carcinoma) metastasis to and within the lung. We believe both of these processes may be critically dependent on integrins.. More detailed descriptions of current projects related to integrins as well as to the cathepsin (endosomal protease) part of the lab, current lab members, and recent publications, are provided within the lab website link (pulmonary.ucsf.edu/chapmanlab).

Pao-Tien Chuang, M.D. , Ph.D. Associate Professor of Biochemistry & Biophysics Research Interests: Cell-cell signaling during mammalian development and in postnatal physiology Summary: Our research aims to understand the molecular program that controls mammalian embryonic development, stem cell maintenance and cancer formation. Accumulating evidence indicates a common mechanism underlying these seemingly disparate processes. We have focused on the Hedgehog (Hh) pathway that plays a key role in many aspects of embryonic development and on dysregulation of Hh signaling that is associated with human birth defects and cancers. We use a combination of genetic, cell biological and biochemical approaches to reveal the molecular mechanisms by which Hh signaling controls various essential cellular processes. Our research will lead to a better understanding of mammalian embryonic development, provide insights into stem cell therapy and facilitate drug development for cancer treatment.

Ronald I. Clyman, M.D. Professor of Pediatrics Research Interests: Cardiology, cell biology, developmental biology, neonatology, neonatal cardiology Summary: The ductus arteriosus is a vital fetal blood vessel that diverts blood away from the fetus's lungs and towards the placenta during life inside the uterus. After birth it is essential that the ductus arteriosus constricts and obliterates itself so that the normal postnatal pattern of blood flow can be established. Essentially all full term infants will have closed their ductus by the third day after birth. Preterm infants of less than 30 weeks gestation have a high chance of having a persistently open or patent ductus arteriosus (PDA). If the ductus arteriosus remains open it contributes to the development of several neonatal morbidities: prolonged ventilator dependency, pulmonary hemorrhage, pulmonary edema, chronic lung disease and necrotizing enterocolitis. Our laboratory has been studying the factors that regulate normal closure of the ductus arteriosus in full term infants and abnormal persistent ductal patency in preterm infants. Approaches used to study this problem are: controlled clinical trials, integrated whole animal physiology, in vitro organ culture, and cell biology.

Leland G. Dobbs, M.D. Adjunct Professor of Medicine and Pediatrics Research Interests: Pulmonary alveolar epithelial development and response to injury, development of biomarkers for the measurement of lung injury Summary: Our laboratory studies the pulmonary alveolar epithelium. More than 99% of the large internal surface area of the lung (in humans ~100-150 m2) is lined by the alveolar epithelium, which is comprised of type I and type II cells, both of which are thought to be essential for mammalian life. Type I cells are very large squamous cells that cover more than 98% of the internal surface area of the lung, providing a narrow anatomic barrier between the air and blood compartments critical for efficient gas exchange. Type II cells are small cuboidal cells characterized by morphologically distinct secretory organelles, lamellar bodies, which contain the intracellular storage pool of pulmonary surfactant. In vivo, type II cells have the capacity to repair injured alveoli, acquiring at least some characteristics of the type I cell phenotype; under these conditions, they appear to transdifferentiate. Current accepted paradigms are that type I cells play a minimal functional role in the lung, but that type II cells perform major alveolar epithelial functions, including acting as progenitor cells during development and after injury. These paradigms do not adequately explain the results of recent experiments in our laboratory. We have developed novel methods for isolating and studying type I cells, which have previously have been resistant to study. Experiments with both in vitro and in vivo models suggest both a major role for the type I cell in ion and fluid transport and revised paradigms for both alveolar epithelial development and response to injury.

Mark D Eisner, A.B., M.D. , M.P.H. Assoc Professor In Residence Research Interests: Title: Epidemiology and health outcomes of obstructive lung disease Key words: asthma, COPD, epidemiology, indoor air pollution, environmental tobacco smoke, secondhand smoke, passive smoking, disability, severe asthma, health outcomes Summary: The burden of obstructive lung disease, which includes asthma and Chronic Obstructive Pulmonary Disease (COPD), continues to increase in the U.S. and around the world. My research program in obstructive lung disease has two central areas: (1) to identify factors that negatively affect the health of adults with asthma, especially those with severe disease and (2) to elucidate how disability develops in COPD. These two parallel lines of investigation are distinct, but mutually reinforcing. In asthma, I am studying how smoking, secondhand smoke exposure, and other environmental exposures affect the health outcomes of adults with asthma. I am also interested in how the process of health care, which includes specialist care, influences health among adult asthmatics. In addition, I am studying how patient-level factors, such as depression and quality of life, impact asthma-related health. A central goal of my research in obstructive lung disease is to prevent deterioration of health status and the development of disability. In a large cohort of patients with COPD, I will elucidate the disablement process in COPD. I have previously shown that adults with COPD have a 10-fold higher risk of disability than members of the general population. However, the current understanding of how disability develops in COPD is limited. In particular, pulmonary function impairment and clinical staging systems do not predict who will develop disability. To elucidate the disablement process, I have established a population-based prospective cohort study of 1200 COPD patients to test a specific conceptual model of how disability develops in COPD. The goal is to provide a scientific basis for the screening and prevention of COPD-related disability.

Joanne N. Engel, M.D., Ph.D. Associate Professor of Medicine and Microbiology & Immunology Research Interests: Bacterial Pathogen-Host Cell Interactions Summary: Infectious diseases are the third leading cause of death in the US and the leading cause worldwide. 95% of all infectious agents enter through mucosal surfaces, such as the linings of the gastrointestinal, respiratory, and genito-urinary tracts. My lab studies the interactions of two bacteria that are important causes of human disease with the mucosal surface. Using a combination of genetics and cell biology, we are studying how Pseudomonas aeruginosa injures host cells and how Chlamydia trachomatis infects human cells. By unraveling the basic mechanisms by which these pathogens cause disease, we may be able to design new drugs, vaccines, or diagnostic strategies. Our studies also reveal new insights into fundamental biologic processes of broad significance.

David J. Erle, M.D. Professor of Medicine Research Interests: Asthma, allergy and inflammation; functional genomics Summary: We are studying how substances produced by the immune system contribute to allergic reactions in the lungs and to asthma, a disease which affects more than 10 million Americans annually. The role of T cell cytokines in murine models of asthma: T helper cells are increased in airways of people with asthma. In animal models, cytokines produced by these cells cause airway inflammation, mucus overproduction, and airway hyperresponsiveness (all of which are hallmarks of asthma). We are working with a variety of mouse models of asthma in order to understand the mechanisms of these cytokine effects. For example, we have produced transgenic mice that lack the capacity to respond to specific cytokines in all cells except airway epithelial cells. These experiments, together with experiments involving cultured human lung cells, allow us to directly determine how the effects of these cytokines on epithelial cells contribute to asthma pathogenesis. Functional genomics: The sequencing of the human genome marks the beginning of a new era in biological research. We are producing tools that allow for the large-scale analysis of gene expression in human and mouse cells and tissues. The current focus is on the production and use of oligonucleotide microarrays. We are working closely with collaborators at UCSF and elsewhere, and are using microarrays to address problems relevant to asthma and other lung diseases.

John Vincent Fahy, M.D. Professor of Medicine Research Interests: Mechanism oriented studies of airway disease in human subjects Summary: Our research involves studies in people with airway diseases such as asthma, cystic fibrosis, and chronic bronchitis. We are involved in clinical trials of new and established treatments on the one hand and in clinical studies designed to improve understanding of mechanism of disease on the other. For clinical trials, we often collaborate with other CVRI investigators or investigators at other institutions to compare the efficacy of new and established drugs. In conducting clinical trials, we are usually interested in exploring the effects of drugs not just on measures of lung function but also on measures of airway inflammation and remodeling. For this purpose, our laboratory has developed expertise in measuring markers of inflammation and remodeling in samples of sputum or in samples of airway fluids and tissue collected during bronchoscopy. Our lab is particularly experienced in measuring gene expression using gene chips and PCR and in quantifying pathology using a rigorous method of quantitative morphology called stereology. For our research on mechanisms of airway disease, we are particularly interested in abnormalities of airway epithelial cells (the lining cells of the airway) and in abnormalities in airway mucus. Mucus abnormalities are common in lung diseases, and we are interested in finding out the specific mucus abnormalities that are characteristic of different lung diseases such as asthma and cystic fibrosis. Recently, we have begun to explore the physical properties of airway mucus - thickness, stickiness, and adhesiveness - using an instrument called a rheometer. The rheology of airway mucus has not been investigated in detail, but the research resources of the CVRI are well suited to making progress in this area. For example, in our clinical laboratories in the CVRI, we can collect induced sputum from volunteers in a carefully controlled way, and in our bench laboratories we can make careful rheological measures. These rheologic measures are allowing personnel in our lab to explore new strategies for breaking up the mucus that normally clogs airways.

Jeffrey R Fineman, M.D. Professor of Pediatrics Research Interests: Endothelial regulation of the pulmonary circulation during normal development and during the development of pediatric pulmonary hypertension disorders. Endothelial dysfunction in pediatric pulmonary hypertension Summary: Pulmonary hypertension, high blood pressure in the lungs, is a serious disorder in subsets of neonates, infants, and children. These include newborns with persistent pulmonary hypertension of the newborn (PPHN), children with congenital heart defects, and teenagers and young adults with primary pulmonary hypertension. The vascular endothelium (the cells that line the blood vessels in the lungs), via the production of vasoactive factors such as nitric oxide and endothelin-1, are important regulators of the tone and growth of pulmonary blood vessels. We utilize an integrated physiologic, biochemical, molecular, and anatomic approach, to study the potential role of aberrant endothelial function in the pathophysiology of pulmonary hypertensive disorders. To this end, we utilize fetal surgical techniques to create animal models of congenital heart disease, and investigate the early role of endothelial alterations in the pathophysiology of pulmonary hypertension secondary to congenital heart disease with increased pulmonary blood flow. Our clinical research interests include the use of pulmonary vasodilator therapy for pediatric pulmonary hypertension, and the use of peri-operative BNP levels as marker of outcome following repair of congenital heart disease.

Stanton A. Glantz, Ph.D. Professor of Medicine Research Interests: Mechanics of cardiac function (experimental and theoretical); environmental tobacco smoke and tobacco control policy Summary: Tobacco is the leading preventable cause of heart disease and heart disease is the leading cause of death due to smoking. We conduct research on a wide range of issues, ranging from the effects of secondhand smoke on the heart through the reductions in heart attacks observed when smokefree policies are enacted, to how the tobacco industry fights against tobacco control programs. In particular, we study the effectiveness of different tobacco control strategies, particularly in the context of large state-run tobacco control programs and international tobacco control issues, with emphasis on how the tobacco industry is working to prevent implementation of meaningful tobacco control policies. We have also identified the importance of young adults (not just teens) as targets for the tobacco industry and efforts at smoking cessation and tobacco use prevention. Our research on the effects of secondhand smoke on blood and blood vessels has helped explain why, in terms of heart disease, the effects of secondhand smoke are nearly as large as smoking. Consistent with what would be expected from the biology of secondhand smoke, we demonstrated a large and rapid reduction in the number of people admitted to the hospital with heart attacks in Helena, Montana, after that community made all workplaces and public places smokefree. Our work in this area was identified as one of the top research advances for 2005 by the American Heart Association.

Samuel Hawgood, M.B., B.S., M.D. Professor and Chair of Pediatrics Research Interests: Structure and function of surfactant apoproteins Summary: Our research activity is focused on the biology of the pulmonary alveolus with a particular emphasis on the structure and function of the pulmonary surfactant apoproteins. The human lung is made up of some 500 million alveoli each with a diameter of 200 microns and a septal wall thickness of only 5-8 microns. The large surface area provided by this foam-like architecture is ideal for rapid respiratory gas exchange but necessitates some unique biological answers to the threat to structural stability posed by the problem of high surface tension and the constant exposure to environmental pollutants, allergens and microbes. Pulmonary surfactant, a lipoprotein secretion of the alveolar epithelial type II cell, stabilizes alveolar structure at low transpulmonary pressures by reducing the retractile surface forces that would otherwise act to collapse the lung at end expiration. The surfactant apoproteins also act as components of the pulmonary innate defense system protecting the lung from inflammation and infection. A derangement of alveolar stability, secondary to a developmental deficiency of surfactant, is the major factor in the pathogenesis of the respiratory distress syndrome of the newborn (RDS). My interest in the biology of surfactant grew from clinical experience in neonatology where RDS is a major cause of neonatal death. I moved to UCSF in 1982 as a research fellow with Dr. John Clements, the scientist who discovered surfactant in the late 1950's. He started his own laboratory, focused on the proteins associated with surfactant, in 1984. By 1985 our laboratory had identified three novel surfactant-associated proteins, now known as SP-A, SP-B and SP-C, and had derived their primary structures from full-length cDNA and genomic clones. In 1993, Erica Crouch in St. Louis described a fourth protein, SP-D. The higher-order structure, genetic regulation, metabolism, and function of these proteins have been the focus of our research since that time. We now know that the surfactant proteins have important roles in the activity of surfactant, particularly the ability to rapidly spread phospholipids at the alveolar surface. The proteins also regulate surfactant turnover and metabolism in the alveolus and play a part in non-antibody mediated response to infection and inflammation in the alveolus. The biology of these proteins is complex and they apparently function as interacting hetero-oligomers to mediate their multiple effects on surfactant biology. At least two of the surfactant proteins, SP-B and SP-C, are present in exogenous surfactants approved for clinical use and fatal human disease has been linked to inherited mutations in both these proteins. This clear link to human disease provides a strong rationale to obtain a detailed understanding of their structure and function.

Stephen C. Lazarus, M.D. Professor of Clinical Medicine Research Interests: Role of inflammation in asthma; mucus hypersecretion Summary: Dr. Lazarus is the Principal Investigator and Co-Investigator of the National Heart, Lung & Blood Institute's COPD Clinical Research Center at UCSF and Asthma Clinical Research Center at UCSF, respectively. Our research thus focuses on these two diseases. Asthma affects 5-10% of the US population, and asthma mortality has increased for several decades. Our laboratory has helped to examine some of the issues that determine how and why different patients with asthma respond differently. We have examined some of the genetic factors that influence response to standard therapy and have found that a significant proportion of the general population has a specific genetic mutation that is associated with a poor response. We have found also that asthmatics who smoke do not respond to steroids as well as non-smokers. We are examining specific ÒpredictorsÓ of response, which if successful will make it feasible to tailor therapy individually for each patient. COPD (chronic obstructive pulmonary disease) is comprised of chronic bronchitis and emphysema and almost always occurs as a result of cigarette smoking. It is the 4th leading cause of death in the United States, and is expected to be the 3rd leading cause of death worldwide by 2020. Other than smoking cessation and oxygen therapy, no intervention has been shown to change the natural history of this disease. We are examining ways to prevent the exacerbations that contribute to progressive loss of lung function. In addition, based on observations made in our laboratory a number of years ago in studies of arachidonic acid metabolism in isolated mastocytoma cells, we are testing whether inhibition of a specific part of this metabolic pathway will speed the resolution of COPD exacerbations, and decrease the duration of hospitalizations for this disease.

Michael A. Matthay, M.D. Professor of Medicine and Anesthesia Research Interests: Alveolar epithelial transport under normal and pathologic conditions Summary: Our research program is focused on discovering new treatments that will improve clinical outcomes in patients with acute respiratory failure from pulmonary edema and acute lung injury. Our work includes experimental studies as well as human-based studies that are designed to learn more about the pathogenesis of acute respiratory failure and to test potential new therapies. Our work is supported primarily by grants from the National Heart, Lung, and Blood Institute.

Jay A. Nadel, M.D. Professor of Medicine and Physiology Research Interests: Signaling mechanisms in airway epithelium Summary: Inhaled bacteria and viruses, as well as irritants such as cigarette smoke, occupational hazardous materials and allergens, are deposited in the airways and result in inflammatory changes. The airway epithelium attempts to defend the organism by mounting defenses, and the airway epithelial surface becomes the ÒbattlefrontÓ of interaction between the ÒinvadersÓ and the epithelial Òdefenses.Ó How does the surface epithelium mount defensive responses? We have shown that in airway epithelium activation of epidermal growth factor receptor (EGFR) leads to the production of mucins, interleukin-8 (a potent neutrophil chemoattractant), and COX2 and cyclooxygenase products. Thus, neutrophils are recruited to the airway lumen, where they can ingest and kill invading bacteria. Subsequently, the secreted mucins trap the bacteria-laden neutrophils and assist in their clearance via cough and mucociliary clearance. How are diverse epithelial cell outcomes governed? EGFR activation is known to be involved in epithelial cell migration, multiplication and differentiation. We have shown that EGFR activation increases mucin production markedly in dense, but not sparse, cultures. Further, we found that the cell surface adhesion molecule, E-cadherin, promotes EGFR- mediated mucin production in a cell density- and cell cycle-dependent fashion via a protein tyrosine phosphatase-dependent EGFR dephosphorylation. Thus, cell surface signaling is responsible for EGFR-dependent cell differentiation. Because the first contact of environmental stimuli (e.g. bacterial products) with the airways occurs at the epithelial luminal surface, we examined potential epithelial molecules capable of intercepting invaders. Airway epithelial cells express EGFR proligands attached to the epithelial luminal surface. We found that activation of metalloprotease TACE causes shedding of EGFR ligand. The released ligand binds to and activates EGFR. This provides a powerful autocrine signaling pathway. TACE is activated by reactive oxygen species (ROS). We discovered that Duox1, a dual oxidase present on the surface of airway epithelial cells, plays a critical role in EGFR activation by releasing ROS, activating TACE, releasing EGFR proligand, causing EGFR activation.

Dean Sheppard, M.D. Professor of Medicine Research Interests: In vivo function of integrins and molecular basis of lung diseases Summary: Our lab studies how a family of proteins (integrins) that provide cells with detailed information about their surroundings contributes to the development of common lung diseases. The lab has made lines of mice missing specific integrins and has found that specific lines are protected from the development of asthma and pulmonary fibrosis (a chronic and usually fatal disease). Some of the lines are also protected in models of the adult respiratory distress syndrome, the most common cause of respiratory failure and a common cause of death in hospitalized patients. Current work in the lab is investigating the molecular mechanisms underlying these effects in order to develop new strategies for treating these challenging (in the case of asthma) or currently untreatable diseases (pulmonary fibrosis and adult respiratory distress syndrome).

Jeanine Wiener-Kronish, M.D. Professor of Anesthesia and Medicine, Vice Chair, Anesthesia Research Interests: Pseudomonas aeruginosa; bacterial-induced lung injury; molecular detection of bacteria; biomarkers of lung injury; ventilator associated pneumonia; bacterial virulence; bacterial biofilms Summary: The Translational Research Group on Microbial Pathogens is a multidisciplinary group of faculty, that includes environmental microbiologists, molecular biologists, bacterial physiologists, epidemiologists and physician scientists dedicated to bringing state-of-the-art scientific techniques to the clinical investigation of human infections. Our faculty involved include: Judith Flanagan, Susan Lynch, and Yuanlin Song, Jeanine Wiener-Kronish, and Hanjing Zhuo. The purpose of our group is to advance the treatment of human infections by investigating the mechanisms of bacterial pathogenesis in patients. The successes of our group include the collection of over 2000 strains of Pseudomonas aeruginosa from respiratory secretions of critically- ill patients and characterization of the strains, using multiple tests, including genotyping, phenotypic assays, biological assays, and sequencing.