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Mast Cell Mediated Cardiac Effects of Particulate Matter

Gregory L. Brower1, Jason D. Gardner1, Joseph S. Janicki1, and Jacob McDonald2
1Auburn University, Auburn, AL; 2Lovelace Respiratory Research Institute, Albuquerque, NM

EPA Grant Number: RD831953

Project Description:

The overall objective of this project is to elucidate the mechanisms responsible for the relationship between particulate matter (PM) exposure and untoward cardiovascular events. Towards this end the following overall hypothesis will be tested: the greater incidence of adverse cardiovascular events associated with increased exposure to PM involves cardiac mast cell degranulation which in turn causes extracellular matrix degradation, ventricular dilatation and reduced cardiac function. The project consists of two specific aims that are designed to test this hypothesis. Throughout the project, our well characterized model of congestive heart failure (CHF) secondary to chronic ventricular volume overload in rats will be utilized. Heart failure is induced by creating an infrarenal aortocaval fistula. The primary objective of this proposal is to determine the contribution of PM mediated mast cell activation to the increased morbidity/mortality due to CHF. In order to determine if individuals are more susceptible to PM mediated cardiac dysfunction, rats in the compensated phase of CHF will undergo controlled acute or repeated exposure to diesel exhaust for 6 hours/day during the progressive development of CHF. At the end of the study period, in vivo hemodynamics, ventricular function, exercise capacity and in vitro diastolic and systolic function will be evaluated. Subsequent histology and biochemical analysis will be performed to evaluate the status of the extracellular matrix; cytokine levels; mast cell density, stage distribution and function; and matrix metalloproteinase activity. The effect of PM exposure on morbidity and mortality will also be assessed. 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 pertaining to this request for proposal will be answered: (1) Does PM exposure accelerate progression to congestive heart failure? (2) Does the cardiac mast cell mediate the adverse cardiac influence of PM exposure? And (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?

 



 



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