Piecemeal degranulation (PMD) of basophils and mast cells plays a central role in the secretion of histamine which is effected by the transport of histamine-loaded vesicles from secretory granules to plasma membrane. In contrast to anaphylactic degranulation, which represents the central cellular event in acute disorders of immediate hypersensitivity, such as anaphylaxis, PMD permits the slow and/or sustained release of mediators. Accordingly, PMD may contribute to the persistence of allergic inflammation associated with IgE-dependent reactions as well as to the sustained inflammation associated with asthma and chronic allergic disorders. Basophils and mast cells that have emptied their granules by PMD also replenish these containers in the absence of expansion of traditional synthetic organelles, such as Golgi structures and rough endoplasmic reticulum. The mechanism(s) for this renewal which serves to extend the functional capabilities of these cells in allergic inflammation is (are) currently unknown. Augmented vascular permeability accompanies allergic inflammation in settings characterized by PMD of basophils and mast cells. A new endothelial cell permeability organelle, the vesiculo-vacuolar organelle (VVO) is the major trans-endothelial cell route by which macromolecules leak from venules exposed to basophil and mast cell mediators. Cellular diapedesis (of neutrophils) in inflammation similarly takes a transcellular route. We propose experiments which rely heavily on sophisticated ultranstructural analyses to test hypotheses generated by our discovery that PMD of basophils and mast cells is associated with histamine secretion in small vesicles and recovery of histamine in granules and that basophil and mast cell mediators (histamine, serotonin, VPF/VEGF) enhance vascular permeability through VVO. Specifically, we will: 1. assess the spatial distribution of RNA in mast cells and basophils; 2. assess the spatial distribution of specific mRNA (TNF-alpha,b-FGF, SCF, IL-4, VPF/VEGF) in human mast cells and basophils undergoing secretion and recovery; 3. assess the formation and function of endothelial cell VVO in allergic inflammation; 4. define the pathway(s) of endothelial cell diapedesis of basophils and eosinophils.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033372-23
Application #
6532689
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1987-04-01
Project End
2005-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
23
Fiscal Year
2002
Total Cost
$350,350
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Melo, Rossana C N; Paganoti, Guillherme F; Dvorak, Ann M et al. (2013) The internal architecture of leukocyte lipid body organelles captured by three-dimensional electron microscopy tomography. PLoS One 8:e59578
Melo, Rossana C N; D'Avila, Heloisa; Wan, Hsiao-Ching et al. (2011) Lipid bodies in inflammatory cells: structure, function, and current imaging techniques. J Histochem Cytochem 59:540-56
Melo, Rossana C N; Spencer, Lisa A; Dvorak, Ann M et al. (2008) Mechanisms of eosinophil secretion: large vesiculotubular carriers mediate transport and release of granule-derived cytokines and other proteins. J Leukoc Biol 83:229-36
Melo, Rossana C N; Dvorak, Ann M; Weller, Peter F (2008) Electron tomography and immunonanogold electron microscopy for investigating intracellular trafficking and secretion in human eosinophils. J Cell Mol Med 12:1416-9
Nagy, Janice A; Dvorak, Ann M; Dvorak, Harold F (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251-75
Wan, Hsiao-Ching; Melo, Rossana C N; Jin, Zhoung et al. (2007) Roles and origins of leukocyte lipid bodies: proteomic and ultrastructural studies. FASEB J 21:167-78
Flaumenhaft, Robert; Rozenvayn, Nataliya; Feng, Dian et al. (2007) SNAP-23 and syntaxin-2 localize to the extracellular surface of the platelet plasma membrane. Blood 110:1492-501
Nagy, Janice A; Feng, Dian; Vasile, Eliza et al. (2006) Permeability properties of tumor surrogate blood vessels induced by VEGF-A. Lab Invest 86:767-80
Melo, Rossana C N; Weller, Peter F; Dvorak, Ann M (2005) Activated human eosinophils. Int Arch Allergy Immunol 138:347-9
Dvorak, Ann M (2005) Ultrastructural studies of human basophils and mast cells. J Histochem Cytochem 53:1043-70

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