Grantee Research Project Results
Final 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. , Murray, David B. , McDonald, Jacob D. , Gardner, Jason D. , Janicki, Joseph S.
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 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 project was to elucidate the mechanisms responsible for the relationship between particulate matter (PM) exposure and untoward cardiovascular events. The overall hypothesis to be tested was that the increased incidence of adverse cardiovascular events associated with exposure to elevated levels of PM is due to cardiac mast cell degranulation, which in turn causes extracellular matrix degradation, ventricular dilatation and depressed cardiac function.
Summary/Accomplishments (Outputs/Outcomes):
The studies performed demonstrate that cardiac mast cells are capable of mediating adverse cardiovascular remodeling resulting from acute PM exposure. The initial studies evaluated the cardiovascular effects of inhaled diesel exhaust particles (DEP SRM 2975) on cardiac mast cells and myocardial remodeling in normal hearts. Male Sprague-Dawley rats were exposed to a nebulized dose of 0.23 mg/ml of DEP in 0.9% saline delivered with 3.5 ml/min O2. Two consecutive days of 20 min daily exposure to DEP caused a significant increase in left ventricular mast cell density (4.0 ± 0.8 vs. 2.1 ± 0.5 cell/mm2 in DEP and saline control respectively, p < 0.05). This increase of cardiac mast cells was coupled with a significant increase in matrix metalloproteinase (MMP-2) activation (154 ± 11 vs. 62 ± 6 arbitrary activity units in DEP and saline control groups, respectively, p < 0.05). In addition to the marked increase in cardiac mast cell density, DEP exposure was associated with collagen fiber degradation and widening of the interstitial spaces between cardiomyocytes indicative of myocardial edema. Treatment with the mast cell stabilizing compound, nedocromil (30 mg/kg/day) significantly attenuated this DEP-induced MMP activation and prevented the morphological alterations in the myocardium.
A subsequent set of studies assessed the acute effects of inhaled diesel exhaust particles on cardiac function. In order to assess the in vivo effects of DEP on cardiac function, male Sprague-Dawley rats instrumented with a Millar pressure/volume conductance catheter advanced into the left ventricle were exposed to DEP by nebulization. The DEP exposure was accomplished in anesthetized, instrumented rats by nebulization of 0.23 mg/ml of DEP as described above. Within 15 minutes of initiating the DEP nebulization, rats developed a significant reduction in developed pressure and cardiac output which was completely prevented 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 exacerbate CHF symptoms in patients with compromised cardiac function and potentiate the development of arrhythmias contributing to sudden cardiac death. 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.
Validation that the cardiovascular effects described above are specific to DEP exposure was derived from a parallel set of experiments delivering PM in the form of cigarette smoke. Rats were sequentially exposed to the smoke from six cigarettes per day and analyzed in the same fashion as those exposed to nebulized DEP. Cigarette smoke PM exposure failed to produce an increase in left ventricular mast cell density and MMP-2 activity was comparable to control. This suggests the possibility that DEP mediated induction of mast cell activation is a direct effect unrelated to nonspecific induction of oxidative stress.
In subsequent experiments, rats in the compensated phase of congestive heart failure underwent controlled acute exposure to diesel exhaust (DE). The studies sought to determine the mechanism(s) by which subchronic diesel PM exposure accelerates cardiac remodeling and the development of CHF utilizing our well-characterized rat model of congestive heart failure. Rats were randomly divided into groups consisting of sham-operated control rats, sham-operated rats exposed to PM, fistula rats and fistula rats exposed to DE. The acute DE exposure of the groups was initiated at 7 wks post-fistula surgery and ventricular function and geometry were evaluated. These acute in vivo DE exposure studies failed to produce distinct differences in the extent of myocardial function or remodeling between these two fistula groups. Both the DE exposed and normal air fistula groups developed comparable ventricular dilatation and functional deficits. This was disappointing, as it was not clear if the DE exposures were just not sufficient to trigger a cardiac mast cell response or if possibly the progressive remodeling characteristic of this rat model of heart failure has already induced a maximal remodeling response that could not be exacerbated.
Still, little was known about the mechanisms responsible for triggering the mast cell mediated cardiovascular dysfunction and adverse remodeling mediated by mast cells in response to DEP exposure. We recently published a paper in Inflammation Research by Morgan et al. reporting a technique to harvest cardiac mast cells from the pericardial space we developed to investigate specific mechanisms responsible for DE PM mediated mast cell activation. This isolation method has been found to be superior to one using collagenase digestion in that the yield of cells obtained is greater and the mast cells remain sensitive to secretagogue stimulation. Therefore, in order to clarify whether mast cells were directly activated by interaction with DEP crossing into the blood stream and entering the cardiac interstitium via coronary perfusion, rat cardiac mast cells isolated using our novel technique reported in the Morgan et al. manuscript were incubated with various concentrations of DEP or the mast cell secretagogue 48/80. Exposure of cardiac mast cells to DEP did not have any effect on histamine release showing that the mechanisms by which mast cells are activated are more complex than simple direct stimulation.
Further, investigations were then conducted using sulfur dioxide, one of the monitored pollutants along with diesel, which has been shown to be one of the major components of pro-allergic pollutants. For example, sulfur dioxide exposure of patients with mild asthma produces severe and acute bronchoconstriction. Previous studies have documented sodium sulfite mediated mast cell activation induced through oxidative stress sensitive pathways. Accordingly, we conducted a series of experiments demonstrating that isolated cardiac mast cells are activated by sulfur dioxide producing a dose-dependent histamine release. Cardiac mast cells were aliquoted and incubated with increasing concentrations of Na2SO3 (0.0, 0.5, 5.0 and 50.0 mM). Antioxidant compounds targeting different mechanisms of free radical generation, including ebselen, dyphenyliodinium (DPI), apocyanin and tocopherol, were incubated with 5.0 mM Na2SO3 in order to determine their efficacy in preventing mast cell degranulation. Sodium sulfite induced a concentration-dependent histamine release from cardiac mast cells of between 25 and 32% (p < 0.05), which was prevented by ebselen and markedly attenuated by DPI. In contrast, the histamine release was completely unaffected by tocopherol under these conditions. These findings indicate that sulfur dioxide is capable of causing cardiac mast cell degranulation via induction of oxidative stress. These findings further suggest that PM mediated induction of oxidative stress may be the mechanism inducing cardiac mast cell activation, thereby inducing myocardial dysfunction and remodeling.
Conclusions:
Taken on the whole, these data represent the first confirmation that cardiac mast cells can 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. Furthermore, the overall findings are consistent with previous findings from our laboratory demonstrating that cardiac mast cells are centrally involved in the progressive adverse myocardial remodeling associated with the development of heart failure. These observations are also consistent with other studies reporting an increase in cardiac mast cell density in canines from polluted urban areas. Given these findings point to specific mast cell mediated mechanism(s) by which elevations in airborne PM appear to induce these adverse cardiovascular effects, specific therapy directed at mast cell stabilization should be evaluated to determine their efficacy in preventing the increased cardiopulmonary-related mortality and hospitalization of cardiac patients associated with elevations in airborne PM.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
Other project views: | All 17 publications | 5 publications in selected types | All 5 journal articles |
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Brower GL, Janicki JS. Pharmacologic inhibition of mast cell degranulation prevents left ventricular remodeling induced by chronic volume overload in rats. Journal of Cardiac Failure 2005;11(7):548-556. |
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Levick SP, Gardner JD, Holland M, Hauer-Jensen M, Janicki JS, Brower GL. Protection from adverse myocardial remodeling secondary to chronic volume overload in mast cell deficient rats. Journal of Molecular and Cellular Cardiology 2008;45(1):56-61. |
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Levick SP, Melendez GC, Plante E, McLarty JL, Brower GL, Janicki JS. Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovascular Research 2011;89(1):12-19. |
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Melendez GC, Voloshenyuk TG, McLarty JL, Levick SP, Brower GL. Oxidative stress-mediated cardiac mast cell degranulation. Toxicological & Environmental Chemistry 2010;92(7):1293-1301. |
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Morgan LG, Levick SP, Voloshenyuk TG, Murray DB, Forman MF, Brower GL, Janicki JS. A novel technique for isolating functional mast cells from the heart. Inflammation Research 2008;57(5):241-246. |
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Supplemental 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.