Cysteinyl leukotriene 2 receptor‐mediated vascular permeability via transendothelial vesicle transport

Abstract

Cysteinyl leukotrienes (CysLTs) are potent mediators of inflammation synthesized by the concerted actions of 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), leukotriene C(4) synthase, and additional downstream enzymes, starting with arachidonic acid substrate. CysLTs produced by macrophages, eosinophils, mast cells, and other inflammatory cells activate 3 different high-affinity CysLT receptors: CysLT(1)R, CysLT(2)R, and GPR 17. We sought to investigate vascular sites of CysLT(2)R expression and the role and mechanism of this receptor in mediating vascular permeability events. Vascular expression of CysLT(2)R was investigated by reporter gene expression in a novel CysLT(2)R deficient-LacZ mouse model. CysLT(2)R was expressed in small, but not large, vessels in mouse brain, bladder, skin, and cremaster muscle. Intravital, in addition to confocal and electron, microscopy investigations using FITC-labeled albumin in cremaster postcapillary venule preparations indicated rapid CysLT-mediated permeability, which was blocked by application of BAY-u9773, a dual CysLT(1)R/CysLT(2)R antagonist or by CysLT(2)R deficiency. Endothelial human CysLT(2)R overexpression in mice exacerbated vascular leakage even in the absence of exogenous ligand. The enhanced vascular permeability mediated by CysLT(2)R takes place via a transendothelial vesicle transport mechanism as opposed to a paracellular route and is controlled via Ca(2+) signaling. Our results reveal that CysLT(2)R can mediate inflammatory reactions in a vascular bed-specific manner by altering transendothelial vesicle transport-based vascular permeability.

Arachidonic Acid Metabolism Regulates Escherichia coli Penetration of the Blood-Brain Barrier

“…3B and C) and next examined whether its enhancement is related to arachidonic acid metabolites derived by 5-LO and FLAP, i.e., LTB4 and cysteinyl LTs. Administration of exogenous cysteinyl LTs (LTD4, 500 ng in 100 l PBS, a dose which increases systemic vascular permeability in mice [27]) 10 min before bacterial injection significantly increased E. coli K1 penetration into the brain in cPLA 2 ␣ Ϫ/Ϫ mice (Fig. 7B) without affecting bacterial counts in the blood, kidneys, and spleens ( Fig.…”

Differential Signaling of Cysteinyl Leukotrienes and a Novel Cysteinyl Leukotriene Receptor 2 (CysLT2) Agonist, N-Methyl-Leukotriene C4, in Calcium Reporter and β Arrestin Assays

“…Its distribution in the human heart and vasculature, adrenal gland, immune cells, brain, and other tissues (Heise et al, 2000;Nothacker et al, 2000;Kamohara et al, 2001;Evans, 2002) suggests that the CysLT 2 receptor is potentially involved in both physiological and pathophysiological processes. In animal models, we have demonstrated that transgenic expression of the hCysLT 2 receptor in vascular endothelium predisposes to heightened myocardial ischemia-reperfusion injury and increased vascular permeability in certain vascular beds Moos et al, 2008). The CysLT 2 receptor has been implicated in allergic and inflammatory diseases such as asthma, rhinitis, and sinusitis (Pillai et al, 2004;Steinke and Borish, 2004), as well as in cerebral inflammation and edema (Di Gennaro et al, 2004).…”

Leukotriene D4activates β2-integrin adhesion in human polymorphonuclear leukocytes

“…Biological activities such as airway hyperresponsiveness [13], cellular adhesion [14][15][16], cell migration [17,18] and mucus secretion [19] are mediated predominantly through cysLT 1 R activation. Whereas cysLT 2 R has been reported to cause vascular permeability [4,20], blockade of cysLT 3 R appears to prevent hypoxic brain injury [12].The 85-kDa cytosolic group IVa phospholipase A2 (gIVaPLA2) is a critical intracellular messenger protein for cellular adhesion and secretion of bioactive lipid mediators in human eosinophils [21,22] and polymorphonuclear leukocytes (PMNs) [16,23]. Activation of gIVaPLA2 causes production of arachidonate metabolites and lysophospholipids [22][23][24][25][26], which are essential for b 2 -integrin adhesion of granulocytes.…”

“…Biological activities such as airway hyperresponsiveness [13], cellular adhesion [14][15][16], cell migration [17,18] and mucus secretion [19] are mediated predominantly through cysLT 1 R activation. Whereas cysLT 2 R has been reported to cause vascular permeability [4,20], blockade of cysLT 3 R appears to prevent hypoxic brain injury [12].…”