title: Cooperative role of endogenous leucotrienes and platelet-activating factor in ischaemia-reperfusion-mediated tissue injury.
abstract: Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4 , cysteinyl-LTs (CysLTs) and platelet-activating factor (PAF). Yet, their potentially cooperative role in regulating I/R-mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre-treated orally with BIIL 284 and/or WEB 2086 and MK-0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre-treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL-8, C5a and zymosan-activated plasma stimulation. However, these agonists elicited LTB4 biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB4 receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB4 and PAF in each other's responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti-inflammatory effect, regulating PMN migration and oedema formation.
authors.affiliation: Department of Clinical Analysis, Toxicology and Bromatology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Bitencourt
authors.forename: Valérie L
authors.initials: VL
authors.lastname: Bessi
authors.forename: David N
authors.initials: DN
authors.lastname: Huynh
authors.forename: Liliane
authors.initials: L
authors.lastname: Ménard
authors.forename: Julie S
authors.initials: JS
authors.lastname: Lefebvre
authors.forename: Tania
authors.initials: T
authors.lastname: Lévesque
authors.forename: Leila
authors.initials: L
authors.lastname: Hamdan
authors.forename: Fanny
authors.initials: F
authors.lastname: Sohouhenou
authors.forename: Lucia H
authors.initials: LH
authors.lastname: Faccioli
authors.forename: Pierre
authors.initials: P
authors.lastname: Borgeat
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marleau
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001681:Biological Assay; D002219:Carbamates / Q000494:pharmacology; D020405:Dermis / Q000473:pathology; D004195:Disease Models, Animal; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000378:metabolism / Q000473:pathology; D005121:Extremities / Q000098:blood supply / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000819:agonists / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000578:Amidines; D001381:Azepines; D002219:Carbamates; D015289:Leukotrienes; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011422:Propionates; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D007975:Leukotriene B4; C059141:verlukast; C424425:amelubant
keywords: Ischaemia/reperfusion; cell trafficking; dermal inflammation; leucotrienes; lipid mediator; myocardial infarction; platelet-activating factor; polymorphonuclear neutrophil