Cysteinyl-leukotrienes receptor activation in brain inflammatory reactions and cerebral edema formation: a role for transcellular biosynthesis of cysteinyl-leukotrienes.
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.
Center for Cardiopulmonary Pharmacology and Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Antonio
A
Di Gennaro
Chiara
C
Carnini
Carola
C
Buccellati
Rossana
R
Ballerio
Simona
S
Zarini
Francesca
F
Fumagalli
Serena
S
Viappiani
Laura
L
Librizzi
Alicia
A
Hernandez
Robert C
RC
Murphy
Gabriela
G
Constantin
Marco
M
De Curtis
Giancarlo
G
Folco
Angelo
A
Sala
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism / Q000503:physiopathology*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D017572:Leukotriene A4 / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008833:Microcirculation; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000502:physiology*; D013189:SRS-A / Q000031:analogs & derivatives* / Q000494:pharmacology; D002722:Chlorobenzenes
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; D001094:Arachidonate 5-Lipoxygenase; D001578:Benzopyrans; D007211:Indoles; D017572:Leukotriene A4; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009419:Nerve Tissue Proteins; D018077:Receptors, Leukotriene; D013189:SRS-A; C071435:BAY u9773; C060893:MK-886; D002722:Chlorobenzenes; C412375:cysteinyl leukotriene receptor 2; C067425:iralukast; C083169:leukotriene D4 receptor