The effects of PM2.5 on allergic inflammation in mast cell deficient mice

by Madison, Sharon L.

MADISON, SHARON LYNN. The effects of PM2.5 on allergic inflammation in mast cell deficient mice. (Under the direction of Bruce Hammerberg.) Animal models of asthma have confirmed epidemiological findings that exposure to fine particulate matter (PM2.5) can enhance asthmatic symptoms, including eosinophilic inflammation and airway hyperresponsiveness. Critics have dismissed the possibility that these studies utilizing artificial exposure scenarios, like intratracheal instillation (i.t.), can be legitimately extrapolated to human risk largely due to the fact that the doses required for this type of model exceed the normal ambient concentrations of PM2.5. In order to improve the credibility of the findings from previous animal studies utilizing the i.t. method for delivery of aqueous particle suspensions to the lung, and to determine the biological mechanisms responsible for the observed enhancement of allergic inflammation following PM2.5 exposure, large-scale air samplers have been developed making it possible to directly expose wild type (WT) and genetically altered mice to fine, concentrated ambient particles (CAPs). In this study allergic asthma was modeled in both WT and mast cell deficient (MCD) mice by local (L) or systemic (S) sensitization to ovalbumin (OVA). Two weeks later mice were challenged with OVA (day 0) and then exposed to CAPs (day 0 & 1) with numerous endpoints collected (day 0-2). Overall, there was a temporal difference in the bronchoalveolar lavage cell profile between L and S sensitized mice, and the contribution of mast cells (MC) to this differential response was best observed for neutrophils at day 0 and day 1. Compared to air exposed mice, CAPs depressed total inflammatory cell infiltrates in the bronchoalveolar lavage fluid at day 0 and day 1 after OVA challenge for all groups. This overwhelming difference of limited cellular infiltration of monocytes and neutrophils in the bronchoalveolar lavage fluid following CAPs exposure, and the significant difference between the L and S sensitization protocols, confound interpretation for all of the factors examined. However, the specific finding that CAPs can enhance eosinophil recruitment by day 2 after OVA challenge indicates that the results from previous animal studies utilizing i.t. PM2.5 exposures do in fact support the epidemiological associations linking PM2.5 exposures with the enhancement of allergic inflammation indicative of the asthmatic phenotype. Given the strict regulation of immunological tolerance at mucosal surfaces like the lung, the genetic variability of different mouse strains, and the daily changes in ambient PM2.5 composition, the findings of this study prompt many unique questions. However, the bottom line is that this study demonstrates that ambient PM2.5 does alter Th2-like responses in mice by enhancing pulmonary BAL eosinophils in the late phase response (day 2), and that mast cells are critical to their recruitment.