Platelet activating factor receptors drive CXC chemokine production, neutrophil influx and edema formation in the lungs of mice injected with Tityus serrulatus venom.
Lung injury is a common finding and a frequent cause of death in cases of severe human envenoming by scorpion sting. The present work investigated the effects of pretreatment with a platelet activation factor receptor (PAFR) antagonist and a CXCR2 inhibitor on the lung injury induced by subcutaneous injection of Tityus serrulatus venom (TsV) in mice. Lung injury was assessed by evaluating the extravasation of Evans blue dye, as an index of increased vascular permeability, the neutrophil accumulation (mieloperoxidase activity), the concentration of tumor necrosis factor-alpha (TNF-alpha) and the chemokine KC in the lung after TsV administration. Neutrophil influx was preceded by the production of KC and dependent on CXCR2, as shown by the ability of repertaxin, a CXCR2 inhibitor, to prevent an increase of MPO activity in the lung. Repertaxin had no effect on TsV-induced lethality. The PAFR antagonist (UK-74,505) significantly reduced TsV-induced vascular permeability changes and neutrophil influx in the lungs. The inhibition of neutrophil influx was associated with inhibition of the production of the CXCR2-active chemokine KC. UK-74,505 had no effect on the lethality induced by TsV. In conclusion, these results show that the influx of neutrophils in the lungs of mice injected with TsV is dependent on the activation of PAFR and on PAFR-dependent production of the chemokine KC as well as activation of CXCR2 on neutrophils. Although lung injury may contribute to late lethality after TsV envenoming, acute lethality is not modified by inhibitors of neutrophil influx.
Coelho
Fernanda Matos
FM
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brasil.
Pessini
Andréa C
AC
Coelho
Amanda M
AM
Pinho
Vanessa S
VS
Souza
Danielle G
DG
Arantes
Eliane C
EC
Teixeira
Mauro M
MM
Teixeira
Antônio L
AL
D000818:Animals; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D012604:Scorpion Venoms / Q000737:chemistry* / Q000633:toxicity*; D012605:Scorpions / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D019743:Chemokines, CXC; D004095:Dihydropyridines; D007093:Imidazoles; D007377:Interleukin-3; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012604:Scorpion Venoms; D013449:Sulfonamides; C404145:myelopoietin; C039351:platelet activating factor receptor; D016179:Granulocyte Colony-Stimulating Factor; C073027:modipafant; C490707:reparixin