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  • Due to cell cell interactions high concentrations of LTs can


    Due to cell-cell interactions, high concentrations of LTs can be locally generated in a short period of time during an inflammatory response, thus potentiating LT function. The cellular communication can be mediated between immune cells as well as between immune cells other cell types. Several studies provided evidence of transcellular biosynthesis of cys-LT through activated neutrophils providing LTA4 to both EC and platelets for production of LTC4, mediating substantial physio-pathological changes in the coronary system [34,35] and respiratory tissue inflammation [36], respectively. It is of note that cellular crosstalk can also stimulate the production of other lipid mediators. For instance, LTA4 produced by neutrophils, can be taken up by platelets and converted into lipoxins via 12-LOX [37] reducing neutrophil recruitment.
    Features shared between AAA and asthma Several studies have revealed that AAA and 412 2 share certain pathophysiological characteristics [[51], [52], [53]]. For instance, components of the inflammatory responses are similar and cells capable of producing cys-LT accumulate in both diseases. Moreover, mouse and human studies suggest that the two diseases are associated [54,55]. In asthma, eosinophils, mast cells and macrophages are regarded as key players, although eosinophils are present in a low number in AAA [56], the potential role of these cells in AAA has remained largely unexplored. Mast cells appear central in the pathogenesis of AAA, they synthesize and release cys-LT, cytokines, chemokines and proteolytic enzymes as well as contribute to the SMC apoptosis [57,58]. Lymphocytes express CysLT1 and it has been reported that activity of this receptor can affect the function of lymphocytes [[59], [60], [61]]. T- and B- lymphocytes produce immunoglobulins and cytokines, activate MMP, which degrade collagen and matrix-proteins by proteolytic cleavage. MMP also activate other immune cells such as macrophages and mast cells. However little has been explored regarding the interplay of CysLT1, lymphocytes and AAA. Likewise, neutrophils express CysLT1. Thus, LTD4 exerts an effect on neutrophils by increasing the production of the cytokine IL-8, which has an important function in the pathogenesis of asthma [62] and possibly in AAA. It is of note that the downstream effect of cys-LT in neutrophils would be more pronounced in the intraluminal thrombus, which is very rich in this cell type, as compared to the vascular wall. Moreover, it has been suggested that LTB4, produced by neutrophils, may play a role in AAA pathogenesis due to its abundance in the thrombus [33,63].
    Montelukast can prevent AAA progression and rupture in vivo Montelukast is typically used for the treatment of asthma and allergic rhinitis, two common morbidities in developed countries affecting about 8% and 14% of the USA population, respectively [64,65]. This agent is a very potent and selective antagonist of CysLT1, which reduces the inflammatory response mediated by cys-LT, especially bronchoconstriction and edema formation. Montelukast was launched in 1998 by Merck (USA) under the trade name Singulair® and exhibited excellent pharmacokinetics, bioavailability and half-life, allowing a single dose regimen. The safety profile of montelukast has been well evaluated in the many long-term studies on large groups of adult and pediatric patients, and no significant side effects have been reported [66]. Studies in our laboratory have demonstrated that cys-LT are involved in AAA pathogenesis both in humans and mice. In surgical specimens of human AAA, the three key components in the biosynthesis of cys-LT, 5-LOX, FLAP and LTC4S were found highly expressed in cells of the wall and thrombus. Additionally, data obtained ex vivo revealed that LTD4 stimulation increased MMP-2 activity and montelukast counteracted this effect, thus suggesting a link between cys-LT and induction of matrix degradation in the AAA wall mediated via CysLT1 [31]. Recently, our laboratory could demonstrate that montelukast is also effective in vivo. We used three well-established, yet mechanistically different, mouse models of AAA (CaCl2, Porcine Pancreatic Elastase and Angiotensin II). Montelukast was delivered intraperitoneally to mice, during 3 or 4 weeks (depending on the AAA model) at the early stages of AAA development and was found to be protective in all three models. This effect might be due to the reduction of MMP-9 and macrophage inflammatory protein-1α (MIP-1α) levels in the aortic wall [32].