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National Center For Environmental Research |  |
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Presentation AbstractMast Cell Mediated Cardiac Effects of Particulate MatterGregory L. Brower1, Jason D. Gardner1, Joseph
S. Janicki1, and Jacob McDonald2 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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