Cooperative role of endogenous leucotrienes and platelet‐activating factor in ischaemia–reperfusion‐mediated tissue injury

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 or...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2013-12, Vol.17 (12), p.1554-1565
Main Authors: Bitencourt, Claudia S., Bessi, Valérie L., Huynh, David N., Ménard, Liliane, Lefebvre, Julie S., Lévesque, Tania, Hamdan, Leila, Sohouhenou, Fanny, Faccioli, Lucia H., Borgeat, Pierre, Marleau, Sylvie
Format: Article
Language:English
Subjects:
Acids
Agonists
Amidines - pharmacology
Animals
Azepines - pharmacology
Biological Assay
Biosynthesis
Carbamates - pharmacology
Cell death
cell trafficking
dermal inflammation
Dermis - pathology
Disease Models, Animal
Edema
Extravasation of Diagnostic and Therapeutic Materials - metabolism
Extravasation of Diagnostic and Therapeutic Materials - pathology
Extremities - blood supply
Extremities - pathology
Inflammation
Inflammation - pathology
Inflammatory diseases
Inflammatory response
Ischaemia/reperfusion
Ischemia
Laboratories
leucotrienes
Leukocyte migration
Leukocytes (polymorphonuclear)
Leukotriene B4 - metabolism
Leukotrienes - metabolism
lipid mediator
Lipids
Male
Mice
Mice, Inbred C57BL
myocardial infarction
Myocardial Ischemia - metabolism
Myocardial Ischemia - pathology
Neutrophil Infiltration - drug effects
Organs
Original
Platelet Activating Factor - metabolism
Platelet Membrane Glycoproteins - agonists
Platelet Membrane Glycoproteins - metabolism
Platelet-activating factor
Platelet-activating factor receptors
Platelets
polymorphonuclear neutrophil
Propionates - pharmacology
Quinolines - pharmacology
Rabbits
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Receptors, Leukotriene - agonists
Receptors, Leukotriene - metabolism
Reperfusion
Reperfusion Injury - metabolism
Reperfusion Injury - pathology
Selectivity
Skin
Tissues
Triazoles - pharmacology
Tumor necrosis factor-TNF
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Summary: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.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.12118