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.

Ubiquinol decreases hemorrhagic shock/resuscitation-induced microvascular inflammation in rat mesenteric microcirculation

“…found that leukotrienes and platelet activating factor (PAF) are important inflammatory mediators that play critical roles in developing microvascular inflammatory response to ischemia‐reperfusion induced by HS and FR (Bitencourt et al. ). Park et al.…”

“…As an antioxidant, ubiquinol decreases ROS levels in the mesenteric microcirculation, thus potentially inhibiting the synthesis and expression of the transcription-dependent adhesion molecule. Bitencourt et al found that leukotrienes and platelet activating factor (PAF) are important inflammatory mediators that play critical roles in developing microvascular inflammatory response to ischemia-reperfusion induced by HS and FR (Bitencourt et al 2013). Park et al found that the release of PAF promoted leukocyte adherence and also stimulated increased generation of ROS especially superoxide from leukocytes.…”

The crucial roles of inflammatory mediators in inflammation: A review

“…Inflitration of white blood cells from circulatory system is essential during inflammatory responses [ 9 , 10 ]. A group of chemotactic agents such as microbial endotoxins holding amino terminal N-formyl methionyl groups, C5a complement fragment, and interleukins along with the secretions of basophils such as platelets activating factor, histamine, and leukotriene B can stimulate intense leukocytes infiltration within few minutes [ 11 , 12 ]. Among the leukocytes, neutrophils are the first inflammatory cells that are recruited at the acute inflammation site [ 13 ].…”

Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?

“…Current anti-inflammatory therapies mainly target the formation and action of inflammatory mediators including LTB4 [ 10 , 11 ]. Consequently, current LTB4-targeting drugs interrupt the progressive recruitment and sustained activation of neutrophils within infarcted myocardium [ 10 , 12 , 13 ].…”