Mast cells (MCs) are recognized as essential effecter cells in the elicitation of the allergic response by releasing cytoplasmic granules, whose contents promote allergic inflammation upon sensitization. Recent biochemical and histological observations suggested that MCs participate in blood-borne leukocyte recruitment, smooth muscle cell (SMC)/endothelial cell proliferation and apoptosis, T-lymphocyte migration and activation, and angiogenesis, essential for the pathogenesis of abdominal aortic aneurysms (AAA), inflammatory disease involving sophisticated cell-cell interaction, inflammatory cell recruitment, cytokine production, immune responses, and matrix remodeling. Although no study has yet been carried out to examine whether AAA formation requires MCs, a role for MCs in atherosclerosis was proposed more than half a century ago. MCs appear in human atheromata. Our recent preliminary data demonstrated, for the first time, the presence of MCs in human and mouse AAA lesions. Deficiency of MCs prevented mice from AAA formation induced by aortic elastase perfusion. While all wild-type (wt, n=11) mice developed AAA, none of the MC-null mice (n=9) did. Importantly, pharmacological stabilization of MC degranulation blocked effectively AAA formation in wt mice. Reconstitution of bone marrow-derived MCs from wt mice (n=12), but not those from IL-6-deficient mice (n=5), restored the AAA phenotypes in MC-null mice, suggesting a direct participation of MCs and their proinflammatory mediators in AAA formation. However, a lack of knowledge in this field and the absence of studies of molecular mechanisms to explain these findings led to a central hypothesis that: MCs are essential to AAA pathogenesis by releasing proinflammatory mediators to participate directly in vascular cell proliferation, apoptosis, angiogenesis, and arterial wall remodeling. We propose three specific aims to test this hypothesis: 1). to examine whether absence of MCs impairs the progression of AAA;2). to identify MC-derived mediators important to the AAA pathogenesis;and 3). To investigate how MCs affect vascular cell biology, and to identify important chemokines responsible for MC recruitment to the diseased aortae in vivo. Together, these lines of experiments should provide both in vitro and in vivo evidence of whether AAA formation requires MCs and possible mechanistic explanations of how MCs might influence this common vascular disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088547-04
Application #
8103212
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$418,375
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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