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Monocycle Chemotactic Protein 1 Is Required for Abdominal Aortic Aneurysm Formation and Repressed by Oral Doxycycline Therapy

Moehle, Christopher William
Thesis/Dissertation; Online
Moehle, Christopher William
Ailawadi, Gorav
Abdominal aortic aneurysm (AAA), the 13 th leading cause of death in 2000 1 , is a burdensome disease with no non-surgical therapeutic options. Better understanding the mechanisms of disease progression is essential to remedying this therapeutic shortcoming. Initial studies into AAA pathophysiology have shown an influx of inflammatory cells including macrophages and neutrophils to be one histological hallmark of the disease. 1 However, the factors regulating these changes are poorly understood. The studies described in this thesis aim to better understand how aortic chemokines, particularly monocyte chemotactic protein 1 (MCP1), regulate AAA progression and cellular composition. MCP1 and its receptor, C-C Chemokine Receptor (CCR) 2, are both associated with monocyte/macrophage chemotaxis in other pathologies. 2, 3 However, inhibiting CCR2 appears to have different effects on AAA than depleting its ligands. 4 We first aimed to definitively resolve the role of MCP1 in AAA by examining elastase-induced experimental aneurysms 5 in MCP1 knockout and wild-type C57bl/6 mice. AAA progression was greatly inhibited by MCP1 knockout. Furthermore, knockout animals displayed a stark absence of aortic Mac2-positive cells and an abundance of intact elastin fibers and smooth muscle contractile proteins. Surprisingly, knockout of MCP1 selectively in bone-marrow derived cells decreased aortic diameter more than global knockout. 6 These novel results led us to hypothesize that a repression of aortic MCP1 may, at least in part, underlie doxycycline's protective effects in AAA. Consistent iii with this hypothesis, both aortic MCP1 and Chemokine (C-X-C motif) Ligand 1 are repressed by oral doxycycline in elastase induced aneurysms. The former effect appears to be at least in part mediated through macrophages, as oral doxycycline greatly decreases the co-localization of MCP1 with Mac2, a commonly used macrophage surface marker. These changes correlate with a near total absence in aortic neutrophils and neutrophil collagenase. Complimentarily, treatment of cultured macrophages with doxycycline inhibits their neutrophil chemotactic ability in a manner that is partially dependent on MCP1 and CXCL1. Taken together with the results of our previous study, MCP1 appears essential to progression of experimental AAA and is at least one mediator of doxycycline's effect on AAA neutrophil number and AAA progression. Note: Abstract extracted from PDF text
University of Virginia, Department of Molecular Physiology and Biological Physics, PHD, 2012
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