Biochemical Laboratory, Dept of Internal Medicine, University of Gießen Lung Center, Justus Liebig University Gießen, Paul Meimberg Straße 5, D-35392 Gießen, Germany.
Eur Respir J. 2010 Nov;36(5):1088-98. doi: 10.1183/09031936.00000309. Epub 2010 Apr 8.
Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids in human lungs upon stimulation with the Ca(2+) ionophore A23187. In this study, we challenged perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl-methionyl-leucyl-phenylalanine (fMLP). Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed by liquid chromatography-mass spectrometry, paralleled by pulmonary artery pressor response and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/cyclo-oxygenase inhibition caused pronounced reduction of AA/fMLP-induced LT/PT synthesis and oedema formation but only limited attenuation of pulmonary vasoconstriction, while inhibition of CYP epoxygenase clearly attenuated AA/fMLP-induced EET/DHET synthesis and vasoconstriction but not oedema formation, suggesting a major contribution of LTs/PTs to vascular leakage and of EETs/DHETs to pressor response. Consequently, generation of EETs/DHETs is greater than that of LTs plus HETEs and PTs in ex vivo perfused human lungs upon microbial challenge suggesting a substantial contribution of these mediators to inflammatory-infectious pulmonary injury.
花生四烯酸（AA）的脂氧合酶、环氧化酶和细胞色素 P450（CYP）产物参与肺血管调节。先前已经描述过 CYP 介导的环氧二十碳三烯酸（EETs）是在刺激 Ca(2+)离子载体 A23187 后人类肺部的主要类二十烷酸。在这项研究中，我们用两种微生物制剂挑战灌注的人肺：大肠杆菌溶血素（ECH）和甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸（fMLP）。两种刺激物都引发了强烈的白三烯（LTs）、羟二十碳四烯酸（HETEs）、前列腺素（PTs）和 EETs/二羟二十碳三烯酸（DHETs）的生成，这通过液相色谱-质谱法评估，同时伴有肺动脉压反应和肺水肿形成。EETs/DHETs 的最大缓冲浓度比 LTs+HETEs 和 PTs 高四倍（ECH）或三倍（AA/fMLP）。5-脂氧合酶/环氧化酶双重抑制导致 AA/fMLP 诱导的 LT/PT 合成和水肿形成显著减少，但肺血管收缩的抑制作用有限，而 CYP 加氧酶抑制明显减弱 AA/fMLP 诱导的 EET/DHET 合成和血管收缩，但不抑制水肿形成，表明 LTs/PTs 对血管渗漏有主要贡献，EETs/DHETs 对升压反应有主要贡献。因此，在微生物刺激下，离体灌注的人肺中 EETs/DHETs 的生成大于 LTs+HETEs 和 PTs，表明这些介质对炎症性感染性肺损伤有实质性贡献。
