Maxadilan, the Lutzomyia longipalpis vasodilator, drives plasma leakage via PAC1-CXCR1/2-pathway

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• 作者：Erik Svensjö ; ^a ; ^{erik.svensjo@gmail.com} ; Elvira M. Saraiva^b ; ^{esaraiva@micro.ufrj.br} ; Rafael Silveira Amendola^c ; ^{rafael.silveira.amendola@gmail.com} ; Christina Barja-Fidalgo^c ; ^{barja-fidalgo@uerj.br} ; Marcelo T. Bozza^b ; ^{mbozza@micro.ufrj.br} ; Ethan A. Lerner^d ; ^{ethan.lerner@cbrc2.mgh.harvard.edu} ; Mauro M. Teixeira^e ; ^{mmtex.ufmg@gmail.com} ; Julio Scharfstein^a ; ^{jscharf2@gmail.com}
• 关键词：fMLP ; (N-formyl-methionine-leucine-phenylalanine) ; MAX ; maxadilan ; M65 ; recombinant mutant of MAX and antagonist of MAX ; PACAP-38 ; pituitary adenylate cyclase-activating peptide ; LTB4 ; Leucotriene B4 ; PCV ; post-capillary venule ; CAP ; capillary ; RFU ; relat
• 刊名：Microvascular Research
• 出版年：2012
• 出版时间：March 2012
• 年：2012
• 卷：83
• 期：2
• 页码：185-193
• 全文大小：1124 K

文摘

Experiments were designed to determine if the vasodilatory peptides maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5 mm²) representative of the hamster cheek pouch microcirculation. Our studies showed that the sand fly vasodilator maxadilan and PACAP-38 induced arteriolar dilation, leukocyte accumulation and plasma leakage in postcapillary venules. The recombinant mutant of maxadilan M65 and an antagonist of CXCR1/2 receptors, reparixin, and an inhibitor of CD11b/CD18 up-regulation, ropivacaine, inhibited all these effects as induced by maxadilan. Dextran sulfate, a complement inhibitor with heparin-like anti-inflammatory effects, inhibited plasma leakage and leukocyte accumulation but not arteriolar dilation as induced by maxadilan and PACAP-38. In vitro studies with isolated human neutrophils showed that maxadilan is a potent stimulator of neutrophil migration comparable with fMLP and leukotriene B₄ and that M65 and reparixin inhibited such migration. The data suggest that leukocyte accumulation and plasma leakage induced by maxadilan involves a mechanism related to PAC1- and CXCR1/2-receptors on leukocytes and endothelial cells.