Mast cells (MCs) have been implicated in gastrointestinal (GI) inflammation and recent evidence suggests the mast cells play an important role in host defense against bacterial infections. But the precise role of MCs in these biological response s have been difficult to define. We developed an approach for analyzing the roles of MCs in vivo using genetically MC-deficient Kit/W/KitW-V mice have been selectively repaired of their mast cell-deficiency. Using this model, we have shown that MCs are essential for the development of neutrophil infiltration and changes in vascular permeability associated with IgE-dependent gastric inflammation. We now propose to further develop this model by deriving MC from TNF-alpha, 5-lipoxygenase (LO)-, or combined TNF-alpha- and 5-HL-deficient mice and using these MCS to reconstitute MC- deficient Kit/W/Kit/W-v mice. This approach will permit us to determine the precise contribution of individual MC mediators (either TNF-alpha TNF-alpha or leukotrienes) to biological responses involving MCS. We will define the contribution of TNF-alpha of TNF- or leukotrienes to the neutrophil infiltration and changes in vascular permeability associated to the neutrophil infiltration and changes in vascular permeability associated with IgE-, and MC-dependent gastric inflammation. We will also determine whether MC-derived TNF-alpha or leukotrienes induce chemokine production in intestinal epithelial cells, including IL-8, eotaxin, MIP-1alpha, and MCP-1 or influence claudin expression. We will determine the participation of P- and E-selectin in the neutrophil recruitment in IgE- and, MC-dependent gastric inflammation and define the role of MCs on P- and E-selectin expression during the response. We will also define the contribution of NC TNF-alpha or leukotrienes in C. difficile toxin A-induced enteritis and the role of MCs in the mortality and neutrophil infiltration caused by Salmonella tyrphimurium infection. Taken together, these studies will provide the first definitive assessment of the importance of individual MC mediators in IgE-dependent gastric reactions, C. dfficile toxin A-induced enteritis, and innate immunity to Salmonella infection.
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