Cardiopulmonary Disease Core (CPDC)

Directors: Howard Kipen, MD, MPH;
                    Paul Lioy, PhD

Members: Tina (Zhi-Hua) Fan, PhD;
Kevin Fennelly, MD;
Nancy Fiedler, PhD;
Panos Georgopoulos, PhD;
Marion Gordon, PhD;
Andrew Gow, PhD;
Sabiha Hussain, MD;
Debra Laskin, PhD;
Jeffrey Laskin, PhD;
Robert Laumbach, MD, MPH;
Kiran Madura, PhD;
Gediminas Mainelis, PhD;
George Rhoads, MD, MPH,
David Rich, ScD;
David Riley, MD;
Stephan Schwander, MD, PhD;
Stuart Shalat, ScD,
Barbara Turpin, PhD;
Daniel Wartenberg, PhD;
Barry Weinberger, MD;
Cliff Weisel, PhD,
Junfeng (Jim) Zhang, PhD

Overview: 
To understand how air pollution adversely affects cardiopulmonary health and to elucidate exposure-response relationships associated with complex gas/particle mixtures found in the atmosphere, CPDC investigators are engaged in interdisciplinary studies ranging from basic science to epidemiology and public health.  Research in this Core is focused on cardiovascular disease and respiratory disease.  During the last three years, Core investigators expanded their previous focus on gaseous air pollutants (VOC’s, ozone), to include effects of particulate air pollution (particulate matter; PM) on acute cardiac and respiratory health effects, reflecting the reality that air pollution is a complex mixture and must ultimately be examined as such in field studies.

Overall Goals:
The overall goal of the CPDC is to determine how critical risk factors, including pollutant exposures (e.g., ozone, PM/diesel exhaust, phthalates, and mixtures), genetic background (e.g., eNOS, GST polymorphisms), intercurrent disease (e.g., diabetes, asthma, heart failure, TB), age (e.g., neonates, elderly), immune status (e.g., genetic or acquired inflammatory mediator defects), and general environment (e.g., stress), interact to contribute to cardiopulmonary morbidity.  The Core seeks to elaborate the pathophysiological events and underlying mechanisms that contribute to disease processes, and to develop response indicators for these conditions and processes. A long-term goal is to use these mechanistic insights and response indicators to evaluate the efficacy of intervention strategies and chemopreventive agents, ultimately driving public health actions and policies to mitigate the adverse effects of air pollution.

Two working groups, characterized by common interests and experimental approaches, address these goals within the Core: 1) Inflammation and Respiratory Disease; and 2) Cardiovascular Disease. The working groups are unified by the vision that understanding, predicting and mitigating the adverse effects of air pollution on human cardiopulmonary health requires not only precise exposure assessment, but also the ability to determine biologically relevant response indicators that delineate host and environmental factors.  
 
Overall Goals of the Inflammation and Respiratory Disease Focus Group:

Short Term:

• Identify biological response indicators of inflammation and oxidative stress associated with the pathogenic mechanisms of pollutant-induced lung injury in humans and in animal models.
• Use bioinformatics approaches to identify specific biological responses that are associated with oxidative stress in human as well as animal strains or species with differential genetic susceptibilities.
• Conduct translational studies using biological response indicators of oxidative stress and inflammation in human field studies (Beijing studies) and CEF studies (PM and ozone).
• Expand CEF studies of inflammatory responses in mild/moderate asthmatics.

Long Term:

• Test hypotheses regarding the role of specific genetic polymorphisms on the differential  susceptibilities to air pollutant induced lung injuries.
• Develop countermeasures to minimize lung injury, initially for sulfur mustard and analogous xenobiotics based on mechanistic discoveries.
• Develop exposure capacity and testable toxicity hypotheses related to nanoparticles, coarse particles, and biological particles for interdisciplinary research.
• Expand clinical investigator strength and translational research through joint training programs for pulmonary medicine and for neonatology.
• Develop specific hypotheses regarding pulmonary disease etiology from participation in the National Children’s Study.

Goals for the Cardiovascular Disease Working Group:

Short Term:

• Elucidate the role of vascular, coagulation, and inflammatory changes as triggers of myocardial infarctions and chronic cardiovascular disease using the Controlled Exposure Facility (CEF), New Jersey commuter traffic, and large urban (Beijing) exposures.
• Explore the utility of novel indictors of vascular change and other cardiovascular endpoints such as blood nitrite/nitrate, arterial tonometry, platelet activation and continuous right heart pressure monitoring.
• Perform case-crossover epidemiology studies of air pollution effects on clinical cardiovascular endpoints in New Jersey and Beijing.
• Develop and test in vitro models of PM-cell interactions relevant to both TB and cardiovascular endpoints.
• Incorporate exhaled breath biological response indicators of pulmonary inflammation from CEF exposures, Beijing, and in NJ field studies.
• Build on relationships with endocrinologists, cardiologists and the CINJ Family Medicine Research Network to expand recruitment of patients with and at risk for heart disease.

Long Term:

• Develop sustained collaborations with cardiologists, applying Core expertise in oxidative stress to their clinical research challenges, while expanding investigations of heart failure and arrhythmia.
• Incorporate the New Jersey MIDAS data set (Myocardial Infarction Data Acquisition System) and the updated, chemical species-specific New Jersey air pollution monitoring data into the IHSFC for Core epidemiology studies.
• Develop animal models for platelet and vascular effects through collaborations with coagulation experts.
• Develop hypotheses regarding cardiovascular disease etiology through the National Children’s Study.
• Use biological response indicators to define mechanisms of pathogenesis and to develop and assess the efficacy of mechanistically based intervention and prevention strategies.
• Core research related to cardiovascular disease, asthma and diabetes will be communicated directly by the COEC in the greater New Brunswick community and through partnerships with the NJ chapters of the American Lung Association and the American Diabetes Association.  

Use of Facility Cores

The IHSFC supported two new controlled exposure pilot experiments (S. Schwander/K. Fennelly, S. Hussain) and facilitated a panel study of physiologic biomarkers in diabetics exposed to road traffic (D. Rich).  The IHSFC also facilitated the logistics of translation of laboratory biomarker techniques to human studies (e.g., A. Gow’s development of nitrite as a biomarker of endothelial dysfunction; K. Madura’s ubiquitin/proteasome pathway assay as a biological indicator of myocardial damage). The IHSFC helped develop and implement complex assays new to environmental health that allow translation of novel endpoints (platelet activation as a marker of procoagulant PM effects).  Moreover, it helped to back-translate the epidemiologically derived hypothesis (e.g., that ultrafine PM directly crosses pulmonary endothelium to increase myocardial infarctions within one hour of a pollution increase) into pilot experiments (M. Gordon and R. Laumbach) to directly test this mechanism in cultured endothelial cells. The IHSFC provides the crucial functions of fractionating, storing, tracking and accessioning of blood and tissue samples for clinical and population studies through the LIMS, and facilitates questionnaire development and data handling for planned epidemiological studies (D. Rich).  Clinical investigators in the Cardiopulmonary Disease Core have historically made extensive use of the Biostatistics, Bioinformatics, and Computational Toxicology Facility Core, in particular relying on their expertise for large clinical exposure trials.  All of the epidemiology and clinical exposure studies, as well as animal studies, use biostatistics support.

The Core has also made extensive use of the Biological Response Indicators Facility Core. Analytical cytometry/image analysis capabilities are critical for traditional flow cytometric analysis of peripheral blood markers and leukocyte activation and for newly incorporated platelet activation assays. The Facility Core also facilitates the work of clinical investigators who lack wet laboratories by performing cell counts and differentials. Confocal microscopy and small animal imaging are utilized by basic scientists for their studies on inflammation and pulmonary disease. The DNA and RNA based technologies of the Biological Response Indicators Core provide expertise preparing and archiving samples for genotyping and gene expression profiling following exposure. RNA from multiple human diesel exposure projects is being archived for eventual gene expression profiling to discover biological response indicators.

Cardiopulmonary Disease Core investigators are heavy users of the Controlled Exposure Facilities in the 1990’s, and were the Principal Investigators of grants that fostered development of the diesel exposure system.  Another major study, an EPA study of susceptibility to fresh aerosols (H. Kipen) is currently being run in the CEF, and two new pilots awarded to Cardiopulmonary Disease Core investigators (S. Hussain; S. Schwander) also use this facility.