Neutrophils and the kallikrein-kinin system in proteinase-activated receptor 4-mediated inflammation in rodents.
1 We evaluated a potential role for proteinase-activated receptor 4 (PAR(4)) in a rodent paw inflammation model, with a focus on two main features of inflammation: (1) oedema and (2) granulocyte recruitment. 2 A PAR(4) antagonist (Pepducin P4pal-10; palmitoyl-SGRRYGHALR-NH(2)) reduced both the oedema and granulocyte recruitment induced by a localized administration of carrageenan in the rat hind paw, pointing to a key role for PAR(4) in this inflammation model. 3 Further, intraplantar injection in the mouse hind paw of a PAR(4) agonist (AYPGKF-NH(2)), but not its standard PAR(4)-inactive peptide control (YAPGKF-NH(2)), caused an inflammatory reaction characterized by oedema (increased paw thickness) and granulocyte recruitment (increased paw myeloperoxidase activity). The PAR(4) agonist-induced effects were inhibited in mice pretreated with pepducin P4pal10. 4 These PAR(4) agonist-mediated effects were not affected by pretreatment with inhibitors of either NO production or prostaglandin release (L-NAME and indomethacin, respectively). 5 However, selective immuno-depletion of neutrophils significantly reduced PAR(4) agonist-induced oedema formation. 6 Moreover, AYPGKF-NH(2)-induced oedema was also reduced by pretreatment with either a kinin B(2) receptor antagonist (icatibant) or a tissue or plasma kallikrein inhibitor (FE999024 and FE999026, respectively), but not with a kinin B(1) receptor antagonist (SSR240612). 7 We conclude: (1) that PAR(4) plays an important role in the inflammatory response as it mediates some of the hallmarks of inflammation and (2) that PAR(4)-mediated oedema is dependent on the recruitment of neutrophils and components of the kallikrein-kinin system.
Houle
Steeve
S
Department of Pharmacology and Therapeutics, Faculty of Medicine, Canadian Institutes of Health Proteinases and Inflammation Network, Mucosal Inflammation Research Group, University of Calgary, Alberta, Canada.
Papez
Martin D
MD
Ferazzini
Mara
M
Hollenberg
Morley D
MD
Vergnolle
Nathalie
N
D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D016234:Kallikrein-Kinin System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D009842:Oligopeptides / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology; D018179:Receptors, Thrombin / Q000502:physiology*
D009842:Oligopeptides; D011453:Prostaglandins; D018179:Receptors, Thrombin; C524864:palmitoyl-seryl-glycyl-arginyl-arginyl-tyrosyl-glycyl-histidyl-alanyl-leucyl-arginine; D009569:Nitric Oxide; D002351:Carrageenan; C112908:protease-activated receptor 4