Mast cells in abdominal aortic aneurysms.
Mast cells (MCs) are proinflammatory cells that play important roles in allergic responses, tumor growth, obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA). Although the presence and function of MCs in atherosclerotic lesions have been thoroughly studied in human specimens, in primary cultured vascular cells, and in atherosclerosis in animals, their role in AAA was recognized only recently. Via multiple activation pathways, MCs release a spectrum of mediators  including histamine, inflammatory cytokines, chemokines, growth factors, proteoglycans, and proteases  to activate neighboring cells, degrade extracellular matrix proteins, process latent bioactive molecules, promote angiogenesis, recruit additional inflammatory cells, and stimulate vascular cell apoptosis. These activities associate closely with medial elastica breakdown, medial smooth-muscle cell loss and thinning, outer media and adventitia inflammation, aortic wall expansion, endothelium erosion, and eventual rupture and thrombosis. Experimental animal AAA models and MC reconstitution technique allowed examination of a direct role of MCs in AAA pathogenesis, and identification of the exact role of each MC-derived molecule. Genetic deficiency of MCs, pharmacological inhibition of MC degranulation, absence of MC-specific chymase and tryptase, or inhibition of these proteases, all effectively attenuated or abolished experimental AAA growth. The role of MCs have been reproduced in humans in several case-control studies, and two cohort studies showing the systemic level of MC specific chymase and tryptase is associated with aneurysmal growth rate, need for later aneurysmal repair and even overall mortality. These observations offer new opportunities to prevent or slow AAA growth in humans, and specific antimastcell drugs inhibiting degranulation of MCs have been used for especially allergic diseases for decades. It clearly calls for randomized clinical trials as no medical treatment to inhibit AAA progression so far have shown to be efficient.
Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. gshi@rics.bwh.harvard.edu
Guo-Ping
GP
Shi
Jes S
JS
Lindholt
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D053802:Tryptases / Q000037:antagonists & inhibitors / Q000378:metabolism
D053818:Chymases; D053802:Tryptases