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Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1α (MIP-1α) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease. [ABSTRACT FROM AUTHOR]

Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are important mediators of asthma, and LTB4 has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC4 synthase (LTC4S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA4 hydrolase, the enzyme responsible for the biosynthesis of LTB4, are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC4S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA4 into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB4. Furthermore, challenge of AAA wall tissue with exogenous LTD4 increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC4S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA. [ABSTRACT FROM AUTHOR]

In humans, heparin-binding protein (HBP) and the potent chemotactic lipid leukotriene B4 (LTB4) are important mediators of innate immune reponses. Here we show that human neutrophils (PMNs) challenged with LTB4 (30 s to 5 mill) release I-IBP as determined by Western blot analysis. This response peaks at 100 nM of agonist and is mediated by the BLT1 receptor. Protein phosphatase-1 (30 µM) and wortmannin (0.5 µM) block the LTB4-mediated HBP release from PMNs, which suggests involvement of the 1-phosphatidylinositol 3-kinase intracellular pathway during degranulation. Furthermore, postsecretory supernatants from LTB4-stimulated PMNs induce intra-cellular calcium mobilization in endothelial cells in vitro and increase in vascular permeability in vivo, as assessed in a mouse model of pleurisy. Selective removal of HBP from the supernatant significantly reduces these activities attributing a key role to HBP in the LTB4-induced change in vascular permeability. This lipid-protein axis could offer novel opportunities for pharmacological intervention in key steps of the vascular response to inflammation. [ABSTRACT FROM AUTHOR]

Evaluates the effect of intravascular activation of neutrophils on the formation of cysteinyl leukotrienes (cysLT) and on the permeability of the cerebral microvasculature. Analysis of perfusion buffers from isolated guinea pig brain in the presence of purified, fMLP-activated neutrophils; Synthesis of cysLT and changes in cerebral vascular permeability; Inhibition of neutrophil leukotriene synthesis.

Introduction: Leukotriene (LT) B(4) is a powerful proinflammatory lipid mediator and triggers adherence to the endothelium, activates and recruits leukocytes to the site of injury. When formed in excess, LTB(4) plays a pathogenic role and may sustain chronic inflammation in diseases such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Recent investigations have also indicated that LTB(4) is involved in cardiovascular diseases., Areas Covered: As the 5-lipoxygenase pathway involves several discrete, tightly coupled, enzymes, which convert the substrate, 'step by step', into bioactive products, several different strategies have been used to target LTB(4) as a means to treat inflammation. Here, we discuss recent findings regarding the development of selective enzyme inhibitors and antagonists for LTB(4) receptors, as well as their application in preclinical and clinical studies., Expert Opinion: Components of the 5-lipoxygenase pathway have received considerable attention as candidate drug targets resulting in one new class of medications against asthma, that is, the antileukotrienes. However, efforts to specifically target LTB(4) have not yet been fruitful in the clinical setting, in spite of very promising preclinical data. Recently, crystal structures along with hitherto unknown functions of key enzymes in the leukotriene cascade have emerged, offering new opportunities for drug development and, with time, pharmacological intervention in LTB(4)-mediated pathologies.

Objective: LL-37, the unique cathelicidin expressed in humans, in addition to acting as an endogenous antibiotic, is an important cell-signaling molecule upregulated in ovarian, breast, and lung tumors. However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment remain elusive. Prostanoids are key regulators of inflammation, and cyclooxygenases (COXs) display proangiogenic activity in vitro and in vivo, mediated principally through prostaglandin E2 (PGE2). Here, we provide evidence for a novel proangiogenic role of LL-37, exerted via activation of endothelial cells and subsequent PGE2 biosynthesis., Approach and Results: LL-37 triggers PGE2 synthesis in endothelial cells in a dose-dependent manner with maximal induction after 4 hours. Endothelial PGE2 biosynthesis was dependent on COX-1, rather than COX-2, as judged by pharmacological inhibition and gene silencing. In vitro matrigel assays supported these findings because LL-37-induced cord formation was abolished by COX-1, but not COX-2, small interfering RNA, and the angiogenic phenotype could be rescued by addition of exogenous PGE2. We find that LL-37 acts on endothelial cells as a potent calcium agonist, inducing phosphorylation and activation of cytosolic phospholipase A2 (cPLA2), promoting a cPLA2→COX-1→PGE2 biosynthetic pathway and subsequent signaling via PGE2 receptor EP3. Moreover, cathelicidin-related antimicrobial peptide, which is the murine ortholog of LL-37, induced prostaglandin-dependent angiogenesis in vivo, which could be blocked by aspirin., Conclusions: Our results identify a novel proangiogenic role of LL-37, suggesting that the axis LL-37/COX-1/PGE2 followed by EP3 signaling is amenable to therapeutic intervention in pathological angiogenesis, for instance by aspirin.