Mast cells and basophils represent critical effector cells in IgE-dependent immediate hypersensitivity responses. While mast cells and basophils importantly contribute to the pathogenesis of acute allergic reactions, these cell types also participate in many other biological responses in which their role is less clear. We wish to evaluate our hypothesis that certain of the important biological functions of basophils and mast cells are expressed via """"""""piecemeal degranulation"""""""" of these cells, in which histamine and other mediators are transported between the cytoplasmic granules and the plasma membrane within small, membrane-bound cytoplasmic vesicles. in contrast to anaphylactic degranulation, which results in the rapid release of large quantities of basophil or mast cell mediators, we have proposed that piecemeal degranulation may permit the slow and/or sustained release of histamine and other basophil or mast cell-derived mediators. Accordingly, piecemeal degranulation of basophils and mast cells may contribute to the persistence of the inflammation which is associated with certain IgE-dependent reaction, such as late-phase reactions, asthma and other chronic allergic diseases, and a wide variety of disorders that are not thought to involve IgE antibodies but which are associated with ultrastructural evidence of piecemeal degranulation of basophils or mast cells. We also wish to evaluate a second hypothesis: that the augmented vascular permeability which has been identified in several types of inflammation, including settings that are characterized by piecemeal degranulation of mast cells or basophils, reflects the enhanced formation and/or function of endothelial cell vesiculo-vacuolar organelles (VVOs), rather than transport through classical inter-endothelial cell gaps such as those which develop in post-capillary venules immediately after the administration of large amounts of histamine. We showed that VVOs represent the major transendothelial cell route by which circulating macromolecules extravasate from tumor vessels. However, their importance in the augmented vascular permeability that is observed in other settings, including those which are associated with piecemeal degranulation of basophils or mst cells, remains to be determined. To test our hypotheses, we will perform in vitro and in vivo experiments to quantify the extent of basophil or mast cell histamine release by piecemeal as opposed to anaphylactic degranulation mechanisms and will perform in vivo experiments to assess the extent to which VVOs, as opposed to inter- endothelial cell gaps, contribute to the augmented vascular permeability that is observed in settings associated with piecemeal as opposed to anaphylactic degranulation of basophils or mast cells.
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