Grantee Research Project Results
2005 Progress Report: Mast Cell Mediated Cardiac Effects of Particulate Matter
EPA Grant Number: R831953Title: Mast Cell Mediated Cardiac Effects of Particulate Matter
Investigators: Brower, Gregory L. , McDonald, Jacob D. , Gardner, Jason D. , Janicki, Joseph S. , Fuseler, John W.
Current Investigators: Brower, Gregory L. , Murray, David B. , McDonald, Jacob D. , Gardner, Jason D. , Janicki, Joseph S.
Institution: Lovelace Biomedical & Environmental Research Institute , University of South Carolina at Columbia
Current Institution: University of South Carolina at Columbia , Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2007
Project Period Covered by this Report: October 1, 2005 through September 30, 2006
Project Amount: $501,250
RFA: The Role of Air Pollutants in Cardiovascular Disease (2003) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Air , Particulate Matter
Objective:
The overall objective of this research project is to elucidate the mechanisms responsible for the relationship between particulate matter (PM) exposure and untoward cardiovascular events. The overall hypothesis to be tested is that the increased incidence of adverse cardiovascular events associated with exposure to elevated levels of PM is caused by cardiac mast cell degranulation, which in turn causes extracellular matrix degradation, ventricular dilatation, and depressed cardiac function.
Progress Summary:
The initial studies evaluated the cardiovascular effects of inhaled diesel exhaust particles (DEP) on cardiac mast cells and myocardial remodeling in normal hearts. Two consecutive days of exposure to DEP caused a significant increase in cardiac mast cell density. This increase in cardiac mast cells was associated with a significant increase in matrix metalloproteinase (MMP-2) activation, interstitial collagen fiber degradation, and widening of the interstitial spaces between cardiomyocytes consistent with myocardial edema. Treatment with the mast cell stabilizing compound, nedocromil, significantly attenuated this DEP-induced MMP activation, as well as prevented the morphological alterations in the myocardium. The acute effects of inhaled DEP on cardiac function were assessed using a Millar pressure/volume conductance catheter advanced into the left ventricle. Within 15 minutes of initiating the DEP nebulization, rats developed a significant reduction in developed blood pressure and cardiac output. These functional changes were blocked completely when rats were pretreated with nedocromil. Taken on the whole, these data indicate that reductions in myocardial contractility following an acute exposure to DEP are mast cell mediated. These data also represent the first confirmation that cardiac mast cells mediate myocardial dysfunction and remodeling in response to acute DEP exposures. Such PM-induced, mast cell-mediated effects on myocardial function could potentiate the development of arrhythmias contributing to sudden cardiac death and exacerbate congestive heart failure (CHF) symptoms in patients with compromised cardiac function. These studies also identify a potential therapeutic approach to prevent the increased cardiopulmonary-related mortality and hospital admissions of patients with cardiovascular disease associated with elevations in airborne PM.
In additional experiments to test the hypothesis that individuals with cardiovascular disease are more susceptible to PM mediated cardiac dysfunction, rats in the compensated phase of CHF underwent controlled acute exposure to diesel exhaust. The preliminary assessment of the functional data did not identify distinct differences in the myocardial function or remodeling between these two groups; however, completion of the subsequent analysis of functional and biochemical parameters have not been completed yet. As such, it is difficult to interpret fully the significance of these preliminary observations. The findings obtained thus far, however, are consistent with prior studies reporting an increase in cardiac mast cell density in canines from polluted urban areas. Further, these findings point to specific mast cell mediated mechanism(s) by which elevations in airborne PM appear to induce these adverse cardiovascular effects.
Future Activities:
The research activity planned during Year 2 of the project initially will be focused on determining the causal relationship between acute diesel PM exposure, mast cell activation, and exacerbation of CHF with a resultant increase in morbidity and mortality. Additional studies seek to determine the mechanism(s) by which subchronic diesel PM exposure accelerates cardiac remodeling and the development of CHF. The extent of myocardial remodeling at 8 weeks postfistula in both the presence and absence of PM exposure will be determined utilizing our well-characterized rat model of CHF. Specifically, rats with arteriovenous fistula will be exposed to repeated sustained elevations of diesel exhaust during the course of myocardial remodeling induced postfistula. Finally, pharmacologic studies will be performed to determine if the adverse effects of PM exposure can be attenuated or prevented. Upon completion of this project, the following questions will be answered: (1) Does PM exposure accelerate the progression to congestive heart failure? (2) Does the cardiac mast cell mediate the adverse cardiac influence of PM exposure? (3) Can the negative cardiac consequences of PM exposure be attenuated or prevented using pharmacological compounds which prevent mast cell degranulation or antagonize endothelin-1?
Journal Articles:
No journal articles submitted with this report: View all 17 publications for this projectSupplemental Keywords:
ambient air, exposure, risk assessment, health effects, vulnerability, enzymes, cumulative effects, pathology,, RFA, Scientific Discipline, Health, Air, Toxicology, particulate matter, Environmental Chemistry, Health Risk Assessment, air toxics, Risk Assessments, Biology, copollutant exposures, atmospheric particulate matter, airway epithelial cells, cardiopulmonary responses, fine particles, acute lung injury, exposure, air pollution, susceptible subpopulations, endothelial function, chronic health effects, ultrafine particulate matter, lung inflammation, oxidant gas, particulate exposure, heart rate, Acute health effects, inhaled, cardiotoxicity, cardiopulmonary, oxidant stress, ultrafine particles, concentrated particulate matter, cardiovascular diseaseProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.