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| - Overview
- Core Director and members
- Key Words
- Research Progress
Overview
Environmental Lung Diseases Research Core is led by Dr. Wayne Mitzner, Professor of Physiology and Dr. Sekhar Reddy, Associate Professor of Physiology, concentrates on the effects of air pollutants and allergens on lung function. These disease effects are often manifested by inflammatory responses, emphysema, asthma, and impaired host defenses. Investigators in this core now have the ability to characterize underlying genetic susceptibility factors that confer increase risk from exposure to these prevalent pollutants. Respiratory illnesses, from lung cancer to emphysema to asthma, affect a large number of people living in urban environments and constitute a major morbidity problem in these populations. The group of researchers in our core bridge experimental and human studies by developing experimental models to explore the mechanisms of action of airborne pollutants. This thrust nicely complements a major thrust of the Center's epidemiologic efforts on the effects of air pollution.
Core Director and members
Dr. Wayne Mitzner, Director and Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Robert Brown, Associate Professor
Dept. of Anesthesiology, Johns Hopkins School of Medicine Dr. Arthur Dannenberg, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Peyton Eggleston, Professor
Pediatrics/Immunology
Johns Hopkins School of Medicine Dr. Allison Fryer, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Joe G.N. Garcia, Professor
Pulmonary
Johns Hopkins School of Medicine Dr. David Jacoby, Professor
Pulmonary, Johns Hopkins School of Medicine Dr. Sekhar Reddy, Co-Director and Assistant Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Ernst Wm. Spannhake, Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Clarke Tankersley, Assistant Professor
Department of Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health Dr. Elizabeth Wagner, Professor
Department of Medicine
Johns Hopkins School of Medicine Key Words
air pollutants, airway constriction, asthma, inflammation, lung disease Progress
The broad goal of the Environmental Lung Diseases Research Core is to define quantitatively the responses of the respiratory system to inhaled particles and pollutant gases, to determine the pathophysiologic mechanisms of these inhalants on pulmonary tissues and cells, and then to interpret these relations in the framework of assessment of risk of human exposure to concentrations that are harmful to human health. For convenience in describing the research supported by Environmental Lung Diseases Research Core, this review will be separated into the five Research Core elements. What follows is a general overview of our progress.
1) Determination of the local concentration of inhaled particulate matter Research work stemming from and EHS pilot grant application 4 years ago led to an RO1 jointly funding Drs. Wagner and Foster to look at how soluble and insoluble particles are cleared from the lung. While most of the insoluble particles on the surface of conducting airways are rapidly cleared (within 24 h) by the mucociliary esacalator, a small fraction is retained for extended periods of time. Soluble particles have been less well studied, but recent work from Wagner and Foster has shown that a surprising fraction of soluble particles are also cleared by the cilia. The largest fraction, however, is cleared from the lung by absorption into the bronchial circulation supplying the airways. As the soluble particle used (DPTA) has a size of 80 nanometers, this model has been further developed into one in which ultrafine particle clearance is now being studied. Though it was at first surprising to find such large particles readily passing into the blood, this observation presents a potential mechanism for how ultrafine particles might cause a depressant cardiovascular response. Work on this topic is being independently pursued by Dr. Tankersley, who will extend this clearance work to lungs of aging mice. Since mice do not have a bronchial circulation, it will be of interest to see how their lungs' clearance compares with larger mammals. Work on this research takes advantage of the EHS Center In vivo Imaging Facility Core, with particular emphasis on the PET scanner.
2) Determination of the molecular, genetic, and inflammatory environment of exposed respiratory tissues and cells
The research concerned with health problems associated with ozone exposure, especially those concerned with factors underlying susceptibility, continues to be a major focus of this Research Core. The work showing an important role for the Toll-like receptor, is being carried out by Dr. Reddy. The effect of genetic regulation is actively being pursued by Dr. Tankersley. His work has involved the mechanism of the role of inhaled particulates and ozone in a unique mouse genetic model. This work is being paralleled with experiments in culture and animal models by Dr. Spannhake. These studies incorporate the very important interaction of viral infections with airborne pollutants, especially ozone. Dr. Spannhake works largely in cell cultures, and new studies are investigating how ozone affects intracellular adhesion molecules, lipid metabolism and mediator synthesis by the airway epithelium. These experiments are being carried out in a novel culture chamber built by our Instrumentation Core that allows exposure of cultured cells to selected uniform concentrations of ozone. These studies have direct impact on our understanding of environmental asthma, a disease that is actively being studied by Dr. Eggleston in the Baltimore community. Discussion with Dr. Eggleston about potential new biomarkers are ongoing.
3) Evaluation of the pathophysiologic mechanisms associated with the effects of these inhalants on pulmonary tissues and cellular responses
A major research effort of this Research Core focuses on an understanding of the basic regulatory mechanisms of airway epithelium and smooth muscle. Much pulmonary disease as well as acute responses to inhaled pollutants involves contraction of airway muscle and subsequent dyspnea. Although diseases like asthma are triggered by allergic and inflammatory stimulation, it is important to recognize that by itself, this would not lead to the salient feature of an asthmatic attack. Without the physiologic end point of airway smooth muscle contraction, asthma might not be the terrible disease that it is. Thus, it is essential to have a solid understanding of the underlying normal physiology of airway smooth muscle and epithelium in order to be able to understand not only asthma, but also the dyspnea and emphysema caused by urban environmental pollutants. It is a major strength of the NIEHS Center that we can readily draw upon the expertise available to analyze the effects of inhaled pollutants on respiratory tissues. Mitzner's work in recent years has been to develop a new imaging method to measure the reactivity of airways in vivo. This work allows analysis and even reconstruction of the airway tree from in vivo HRCT images. This approach uses a method to assess local heterogeneity of the airways in response to a host of challenges and insults. Experimental work has for the first time shown the ability to localize the effect of ozone induced inflammation in the airway tree. This intra-programmatic collaborative study with Dr. Brown will continue in the coming year in an effort to understand the heterogeneous response already observed in individual airways in vivo following acute ozone exposure. Before her departure, Dr. Fryer was studying the role of abnormalities in the parasympathetic innervations of the airways. Initially funded as a pilot project and using the inhalation facility, she was able to show that ozone damages the M2 muscarinic receptor in the airways. Ongoing studies are focusing on the interaction with viral infection, and possible neural repair processes. These studies will continue with an Adjunct appointment. She has made use of the Exposure and Health Effects Assessment, Cell and Tissue Analysis and Bioinformatics and Biostatistics Facility Cores and collaboration with Drs. Spannhake and Jacoby.
Since the epithelium is the first lung tissue attacked by pollutants, knowledge of normal epithelial function is essential. Aberrant cell proliferation and differentiation following toxic injury to bronchial epithelium can lead to the development of various respiratory diseases including lung cancer, but the underlying molecular mechanisms involved in such processes remain enigmatic. The co director of this Research Core, Dr. Reddy, is working on gene expression and regulation during toxicant induced airway epithelial injury-repair and transformation. Exposure to cigarette smoke (CS) can lead to the development of lung cancer and other respiratory diseases such as emphysema, but the molecular mechanisms underlying these processes remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiological and pathophysiological processes, Dr. Reddy lab is investigated the effects of CS on Jun and Fos family member expression and regulation in pulmonary epithelial cells. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with airway squamous metaplasia and tumor progression, his lab further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, treatment of cells with an epidermal growth factor receptor (EGFR)-specific inhibitor completely suppressed CS-stimulated fra-1 expression suggesting a prominent role for EGFR-mediated signaling in CS-promoted respiratory pathogenesis. Currently, his lab is using both in vivo and in vitro models to understand the role and biology of AP-1 family of transcriptional factors and upstream signaling pathways in respiratory pathogenesis. Oxidative stress plays a major role in hyperoxia-induced acute lung injury. Reddy and Steve Kleeberger (who is now at NIEHS) laboratories previosuly showed that mice lacking the NF-E2-related transcription factor 2 (Nrf2) are more susceptible to hyperoxia than wildtype mice. Nrf2 activates antioxidant response element (ARE)-mediated gene expression involved in cellular protection against toxic insults. Currently, in collaboration with Kleeberger, his lab is investigating the mechanisms that control activation of Nrf2 by hyperoxia. Dr. Reddy's work on basic molecular and cellular mechanisms on bronchial carcinogenesis and oxidant induced lung injury compliments ongoing studies of Dr. Biswal (Molecular Toxicology Research Core), who is working on chemoprevention against acrolein induced lung cancer development and cigarette smoke promoted respiratory pathogenesis, such as emphysema. In addition, this new Core's interest in potential control of lung tumors is directly related to new studies by Mitzner, Wagner, and Biswal (Molecular Toxicology Core), which involve a mouse model of lung angiogenesis. A recently funded pilot project is involved with using the Affymetrix gene chips to investigate the temporal and differential expression of genes in a well control mouse model. Based on this pilot data, an NIH RO1 was recently funded with a 1.1% priority. A major new initiative was begun to investigate the reasons underlying the increased morbidity and mortality associated with increased airborne particulates. Although the epidemiology is quite convincing, the underlying mechanisms are not at all clear. Two years ago we began a NIEHS Center supported informal discussion group to present articles and experimental data related to particle exposures in humans and experimental models. Dr. Tankersley's most recent data shows a potentially important role of Atrial Natriuretic Peptide in the cardiac response to airborne particulate matter. This pilot data has formed the basis of an RO1 application that was recently funded with high priority from NIH.
4) Interpretation of these relations in terms of health assessments from human exposures
Human studies comprise a Research Core element that was initially begun as a direct outcome of this EHS Center. Work in this area continues with Dr. Brown, Dr. Spannhake, and Dr. Garcia. Dr. Spannhake is involved in studies of lavage samples from experimental subjects. Dr. Garcia heads a genomics center grant, and will continue work assessing the mechanism of hyperoxic toxicity in human subjects. His lab collaborates with Dr. Spannhake on the mechanism of hyperoxic lung injury.
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