Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Abstract

Abstract-Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (ϩ/ϩ) rats following periaortic application of calcium chloride (CaCl 2 ) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA. Key Words: adventitia Ⅲ inflammation Ⅲ mast cell Ⅲ matrix metalloproteinase Ⅲ aneurysm A bdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration. 1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States. 3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA. 2,4 -8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators. 9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases, 10 as well as by recruiting other inflammatory cells, such as neutrophils, macrop...

Mast cell density and distribution in human abdominal aortic aneurysm

“…Circulating mast cell precursor has been reported to mature in tissues by SCF (Zsebo et al 1990) and other cytokines such as IL-4 (Conti et al 2003;Yanagida et al 1995). In accordance with the report (de Paulis et al 1999), we have shown that the immunoreactivity of SCF was detected in the cytoplasm of mast cells (Tsuruda et al 2008), suggesting autocrine or paracrine regulation of differentiation and maturation of cells in aortic tissues. Schönbeck et al (2002) showed the augmented expressions of IL-4 and IL-10 in inflammatory cells of AAA tissues.…”

“…More importantly, we demonstrated that the cell number was significantly increased at the outer media and adventitia of AAA, compared with either the early or advanced stage of atherosclerosis. The proportion of activated mast cells (seen as "degranulation") has been reported to be frequently observed in the adventitia of AAA compared to in advanced atherosclerosis (15±2 % vs. 0.4±0.3% total number of mast cells) (Tsuruda et al 2008). Thus, mast cells distributed "outside of aortic wall" appear to be associated with the AAA pathogenesis.…”

“…Denatured protein extract (30 µg) from the AAA and non-dilated atherosclerotic aorta was subjected to sodium dodecyl sulfate-polyacrylamide gel as described (Tsuruda et al 2008). …”

“…On the other hand, mast cell chymase may have a wide range of actions in AAA tissues: induction of apoptosis of smooth muscle cells (Leskinen et al 2001), conversion of angiotensin I to angiotensin II (Takai et al 1999) and of pro-MMP-2 and -9 to the mature forms (Tchougounova et al 2005), whereas mast cells themselves are found to express MMPs-2 and 9 (Fang et al 1999). We have reported that interferon-γ produced from mast cells stimulated MMP-9 synthesis by macrophages in the co-culture (Tsuruda et al 2008). Angiogenesis appears to be another important histopathological characteristic of AAA (Paik et al 2004;Reeps et al 2009).…”

“…Based upon the observation in human tissues, we propose that mast cells infiltrating at the outer media and adventitia of the AAA wall contribute to the development or progression of aneurysm formation, coordinating with other inflammatory cells. Furthermore, the inhibition of mast cell accumulation, maturation and activation in the aortic wall with a mast cell stabilizer would be a potential pharmacological target for preventing/attenuating the development of AAA (Tsuruda et al 2008;Sun et al 2007). …”