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  • thymidine phosphorylase Cys LT have been shown to be

    2021-01-22

    Cys-LT have been shown to be critical for stimulation of monocytes to produce various proinflammatory factors [32,67]. Fig. 3 shows results obtained with human peripheral monocyte-derived macrophages differentiated for 6 days with 20 ng/ml macrophage colony-stimulating factor (M-CSF) and challenged as described in references [27] and [32]. Montelukast significantly inhibits LTD4-induced mRNA expression of tumor necrosis factor (TNF) α, while a similar trend was observed for IL-1β mRNA expression. Challenge with LTD4 did not affect mRNA levels of IL-10. These data show the potential of this drug to regulate human macrophage functional responses.
    Repurposing an anti-asthma drug for non-invasive treatment of AAA As the insights to the pathophysiological processes have increased, molecular targets have been identified that potentially could be used for development of AAA treatments. However, in order to suppress aneurysm growth, drugs would have to be administered over long periods without causing serious adverse effects. These considerations have limited the number of realistic drug candidates, but still the concept of pharmacological management of AAA is very attractive. It is of note the efforts worldwide to find a non-invasive therapeutic to treat AAA development. As an example, other classes of drugs, for instance doxycyclin an antibiotic inhibitor of MMP, the β-blocker atenolol and the mast cell stabilizer pemirolast have not demonstrated any significant clinical effect [[68], [69], [70]]. The experience obtained from these trials suggest that it is necessary to improve the preclinical assessment of the drug, especially with regards to its availability and actions within the complex, degenerative and inflamed vessel wall as well as the non-vascularized thrombus. Montelukast is a standard and safe drug for treatment of thymidine phosphorylase and allergic rhinitis, and until now it has never been tested as treatment for AAA. Therefore, the results obtained from our basic research might offer hope to patients with AAA and pave the way for repurposing a safe drug for a serious and potentially fatal vascular disease. In this context, it is worth noting that montelukast is also tested in clinical trials for treatment of other disorders such as sickle cell anemia, Alzheimers disease, and multiple sclerosis (www.ClinicalTrial.gov)
    Conclusions AAA is a serious, life-threatening disease with a major socio-economic impact and the rating of aneurysm growth and the risk of rupture are both exponentially related to aneurysm size [1]. Since AAA is associated with high morbidity and mortality, screening programs for AAA detection have been widely implemented for more than a decade. These programs intend to reduce overall mortality by initiation of preventive actions (i.e. cessation of smoking, reduction of blood pressure) and elective surgery in eligible patients, thus being highly cost-effective from a public health perspective [71]. We have presented data indicating that the asthma drug montelukast may be used in AAA. The prospect of identifying a safe, well tolerated, and inexpensive medicine that can retard and prevent aneurysm growth, holds promise as a major medical advance that would reduce and delay the need of risky and expensive surgery, prolong the life expectancy, and increase the quality of life for patients suffering from AAA.
    Conflict of interest
    Acknowledgements This work was supported by grants from the Swedish Research Council (10350; Linneus Grant CERIC) the Novo Nordisk Foundation (NNF15CC0018346 and NNF15CC0018486), and a Distinguished Professor Award from Karolinska Institutet.
    Cysteinyl leukotriene receptor 1 (CysLT1) is a member of the G protein-coupled receptor family, implicated in inflammatory pathologies such as asthma. Since signalling potential of CysLT1 may depend on its internalization pathway and intracellular trafficking, these pathways were studied in the present report.