Cysteinyl‐leukotriene receptor activation in brain inflammatory reactions and cerebral edema formation: a role for transcellular biosynthesis of cysteinyl leukotrienes

Abstract

We studied the effect of intravascular activation of human neutrophils on the synthesis of cysteinyl leukotrienes (cysLT) and the formation of cerebral edema in guinea-pig brains. Challenge with the chemotactic formylated tripeptide fMLP (0.1 microM) of neutrophil-perfused brain in vitro resulted in blood-brain barrier disruption associated with a significant increase of cysLT. Both events were completely prevented by neutrophil pretreatment with a specific 5-lipoxygenase (5-LO) inhibitor. Perfusion with the 5-LO metabolite leukotriene B4 (10 nM), together with neutrophils treated with the 5-LO inhibitor, did not restore the alteration in permeability observed upon perfusion with untreated and activated neutrophils. The dual cysLT1-cysLT2 receptor antagonist BAYu9773 was more potent and more effective than a selective cysLT1 antagonist in preventing the brain permeability alteration induced by neutrophil activation. RT-PCR showed significant expression of cysLT2 receptor mRNA in human umbilical vein endothelial cells. Intravital microscopy in mice showed that inhibition of leukotriene synthesis significantly reduced firm adhesion of neutrophils to cerebral vessels without affecting rolling. These data support the hypothesis that neutrophil and endothelial cells cooperate toward the local synthesis of cysLT within the brain vasculature and, acting via the cysLT2 receptor on endothelial cells, may represent a contributing pathogenic mechanism in the development of cerebral inflammation and edema.

Eicosanoid Transcellular Biosynthesis: From Cell-Cell Interactions to in Vivo Tissue Responses

“…When such brain preparations were infused with human neutrophils that had been primed with GM-CSF (1 nM) followed by addition of fMLP (100 nM) to the infusion buffer, a substantial amount of LTD 4 was found to be released into the perfusate as identified by specific mass spectrometric techniques. In addition, there was evidence for the production of LTB 4 and nonenzymatic products of LTA 4 hydrolysis (Di Gennaro et al, 2004). These results were consistent with the generation of LTA 4 by the neutrophils present in the perfusion media followed by brain endothelial cell uptake and metabolism into LTC 4 .…”

“…Recently, the potential for transcellular biosynthesis taking place in the brain was examined in the isolated perfused guinea pig brain with an intact and functional vascular endothelial barrier (Di Gennaro et al, 2004). When such brain preparations were infused with human neutrophils that had been primed with GM-CSF (1 nM) followed by addition of fMLP (100 nM) to the infusion buffer, a substantial amount of LTD 4 was found to be released into the perfusate as identified by specific mass spectrometric techniques.…”

Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation

“…Transcellular synthesis of cysLTs has been shown in heterologous perfusion models with human neutrophils and rabbit hearts or guinea pig brains (40,41). This report provides unequivocal evidence of transcellular cysLT production in an in vivo model of inflammation in a single organism.…”

Cysteinyl Leukotrienes Enhance the Degranulation of Bone Marrow-Derived Mast Cells through the Autocrine Mechanism

“…Cysteinyl LTs are released from leukocytes in the early phase of the inflammatory response and serve as contractile agonists for tissues that contain smooth muscles, such as blood vessels and bronchi. Besides their role as contractile agonists, cysteinyl LTs stimulate various cells and exert pleiotropic effects such as hematopoiesis, cellular migration (Bautz et al 2001), leukocyte adhesion to endothelial cells (Kanwar et al 1995;Pedersen et al 1997;Nagata et al 2002;Di Gennaro et al 2004), chemoattraction (Laitinen et al 1993;Spada et al 1994), cell proliferation, and cell survival (Jiang et al 2006;Vannella et al 2007;Bosse et al 2008). In the pathological context, cysteinyl LTs play important roles in the manifestation of allergic symptoms; therefore, receptor antagonists against cysteinyl LTs are widely used for anti-allergic therapy.…”