PAF-induced synthesis of tetraenoic and pentaenoic leukotrienes in the isolated rabbit lung

被引:17
作者
Grimminger, F [1 ]
Mayer, K [1 ]
Kiss, L [1 ]
Walmrath, D [1 ]
Seeger, W [1 ]
机构
[1] Univ Giessen, Dept Internal Med, D-35392 Giessen, Germany
关键词
neutrophils; inflammation; lipid mediators; platelet-activating factor;
D O I
10.1152/ajplung.2000.278.2.L268
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
In an isolated rabbit lung model, we tested the hypothesis that platelet-activating factor (PAF)induced leukotriene (LT) synthesis is critically dependent on the free precursor fatty acid supply and the possible substitution of arachidonic acid (AA) by eicosapentaenoic acid (EPA). To augment the intravascular polymorphonuclear neutrophils (PMNs) in the isolated lung, human PMNs were infused into the pulmonary artery. LTs and hydroxyeicosatetra(penta)enoic acids were quantified with HPLC techniques, Application of PAF (5 mu M) or AA(10 mu M) provoked the generation of limited quantities of 4-series LTs and 5-hydroxyeicosatetraenoic acid (total sum of 5-lipoxygenase products approximate to 7 and approximate to 27 pmol/ml in lungs both with and without infused PMNs, respectively). Combined administration amplified 5-lipoxygenase product formation, with a predominance of cysteinyl-LT synthesis in lungs both without (total sum approximate to 67 pmol/ml) and, much more strikingly, with (total sum approximate to 308 pmol/ml) an infusion of neutrophils. EPA(10 mu M) elicited exclusive generation of 5-series Lm and 5-hydroxyeicosapentaenoic acid (total sum approximate to 82 pmol/ml). Dual stimulation with PAF and EPA provoked amplification of EPA-derived 5-lipoxygenase product formation, again. with predominance of cysteinyl-LTs in lungs without (total sum approximate to 224 pmol/ml) and, in particular, with (total sum approximate to 545 pmol/ml) preceding microvascular PMN entrapment. Combined application of PAF, AA, and EPA resulted in the synthesis of LTs derived from both fatty acids, with a predominance of 5-series products. We conclude that the PAF-evoked 5-lipoxygenase product formation in the neutrophil-harboring lung capillary bed is critically dependent on intravascular precursor fatty acid supply, with EPA representing the preferred substrate compared with AA. PMN-related transcellular eicosanoid synthesis is suggested to underlie the predominant generation of cysteinyl-LTs. The supply of n-3 versus n-6 precursor fatty acid may thus have a major impact on inflammatory mediator generation.
引用
收藏
页码:L268 / L275
页数:8
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