Maxadilan, the Lutzomyia longipalpis vasodilator, drives plasma leakage via PAC1-CXCR1/2-pathway.
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 (5mm(2)) 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 B(4) 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.
Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil. erik.svensjo@gmail.com
Erik
E
Svensjö
Elvira M
EM
Saraiva
Rafael Silveira
RS
Amendola
Christina
C
Barja-Fidalgo
Marcelo T
MT
Bozza
Ethan A
EA
Lerner
Mauro M
MM
Teixeira
Julio
J
Scharfstein
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D002610:Cheek / Q000098:blood supply*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D003911:Dextrans / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009154:Mutation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D011576:Psychodidae / Q000737:chemistry; D023062:Receptors, Interleukin-8A / Q000187:drug effects* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000187:drug effects* / Q000378:metabolism; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012235:Rhodamines / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000302:isolation & purification / Q000494:pharmacology*; D014699:Venules / Q000187:drug effects / Q000378:metabolism
D003911:Dextrans; D005456:Fluorescent Dyes; D019476:Insect Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011994:Recombinant Proteins; D012235:Rhodamines; D014665:Vasodilator Agents; C015219:fluorescein isothiocyanate dextran; C069147:maxadilan protein, insect; D016650:Fluorescein-5-isothiocyanate