Challenging the evidence for hepoxilin A3 being a mediator of neutrophil epithelial transmigration.
Challenging the evidence for hepoxilin A3 being a mediator of neutrophil epithelial transmigration.
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质疑赫泊西林 A3 是中性粒细胞上皮迁移介质的证据。
DOI：
10.1152/ajplung.00349.2020
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Brash,AlanR
中科院分区：
文献类型：
--
作者：
Brash,AlanR
编者按：从2004年开始到目前为止的一系列文献中，涉及二十烷类肝素A3(HxA3)是肺或胃肠道(GI)上皮细胞对细菌感染反应产生的中性粒细胞趋化反应的介体(1，2，4-6，8，9，11，16-18)。因此，HxA3的产生及其作为趋化因子的生物活性被认为是跨上皮中性粒细胞(PMN)募集到粘膜炎症部位的关键最后一步，也是炎症反应的重要组成部分。趋化介质的生物合成涉及花生四烯酸的释放和12-脂氧合酶通过中间体12-羟基-二十碳四烯酸(12-HPETE)的转化，生成环氧羟基衍生物HxA3。以下对已发表的证据的综述挑战了HxA3被正确地确定为肺和胃肠道上皮细胞趋化反应的介体的论点。对证据的批判性综述发现了以下缺陷：1)在最初的发表(9)中，分离的趋化因子在分析性质上没有与HxA3(或任何可信的标准)进行比较，也没有显示出分离的因子具有生物活性；一份相同或相似分析的早期报告指出，在刺激的上皮细胞单层中检测到210pmolHxA3(71 Ng)，在对照组中检测到1pmolHxA3，但没有提供实验记录(5)，在随后的论文中使用定量LC-MS分析，HxA3的数量减少了约1000倍(尽管来自未指明的体积或数量的上皮细胞)(4，17)。HxA3是两个可层析分离的羟基异构体(8R-和8S-羟基)的混合物(10)，而单峰被鉴定为PMN迁移介体(9)。PLA2参与了这一途径，但没有发现HxA3的形成(7)。2)在最初的出版物(9)中，白三烯B4(LTB4)可能是天然因子的可能性被驳回，理由是除了其趋化活性外，LTB4还能使白细胞脱粒，而天然因子不能；然而，与其强大的趋化活性相比，LTB4是一种弱的中性粒细胞促分泌剂(3、13、14)，在2004年美国国家科学院院刊的论文中检测到它的浓度为500 ng/mL(9)，比显示趋化所需的浓度高出约三个数量级。3)真品HxA3表现出弱的趋化活性，并且在可比的剂量-反应曲线中，其效力约为LTB4的100-1000倍，且效力更低(6)；4)与效力的这种差异一致，
TO THE EDITOR: A series of papers in the literature, beginning in 2004 and up to the present, implicate the eicosanoid hepoxilin A3 (HxA3) as the mediator of neutrophil chemotaxis produced by lung or gastrointestinal (GI) epithelial cells in response to bacterial infection (1, 2, 4–6, 8, 9, 11, 16–18). The production of HxA3 and its biological activity as a chemotactic factor is thus cited as a key final step in the trans-epithelial polymorphonuclear leukocyte (PMN) recruitment to sites of mucosal inflammation and an important component of the inflammatory response. Biosynthesis of the chemotactic mediator is proposed to involve the release of arachidonic acid and its transformation by 12-lipoxygenase via the intermediate 12-hydroperoxy-eicosatetraenoic acid (12-HPETE), producing the epoxy-hydroxy derivative HxA3. The following review of the published evidence challenges the contention that HxA3 is correctly identified as the mediator of this chemotactic response in the lung and GI epithelium.A critical review of the evidence finds shortcomings in that, 1) in the initial publication (9) the isolated chemotactic factor was not compared in analytical properties to HxA3 (or to any authentic standard) nor was the isolated factor shown to possess biological activity; an early report of the same or similar analyses states that 210 pmol HxA3 (71 ng) was detected in stimulated epithelial cell monolayers and 1 pmol in controls, but no experimental recordings are presented (5) and in subsequent papers using quantitative LC-MS assays the amounts of HxA3 are reduced by approximately a thousand-fold (albeit from unspecified volumes or numbers of epithelial cells)(4, 17). HxA3 is a mixture of two chromatographically separable hydroxy isomers (8R-and 8S-hydroxy)(10), whereas a single peak was identified as the PMN migration mediator (9). PLA2 was implicated in the pathway although HxA3 formation was not demonstrated (7). 2) In the original publication (9) the possibility that leukotriene B4 (LTB4) could be the natural factor was dismissed on the grounds that, in addition to its chemotactic activity, LTB4 degranulates leukocytes whereas the natural factor does not; however, compared with its potent chemotactic activity, LTB4 is a weak neutrophil secretagogue (3, 13, 14), and in the 2004 Proceedings of the National Academy of Sciences USA paper it was tested at 500 ng/mL (9), about three orders of magnitude higher than the concentration required to exhibit chemotaxis. 3) Authentic HxA3 exhibits weak chemotactic activity and in comparable dose-response curves is about 100–1,000 times less potent than LTB4 and lower in efficacy (6); 4) in line with this difference in potency,
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影响因子：
3.3
作者：
S. Rae;M. J. Smith
通讯作者：
S. Rae;M. J. Smith
DOI：
10.1152/ajplung.00147.2010
发表时间：
2011-02-01
影响因子：
4.9
作者：
Hurley, Bryan P.;Pirzai, Waheed;McCormick, Beth A.
通讯作者：
McCormick, Beth A.
合成白三烯 B4 是一种有效的趋化因子，但对人类中性粒细胞 (PMN) 的促分泌剂较弱。
DOI：
10.1016/0090-6980(83)90110-7
发表时间：
1983
期刊：
Prostaglandins
影响因子：
--
作者：
T. Rollins;B. Zanolari;M. Springer;Yvon Guindon;R. Zamboni;Lau Cheuk;J. Rokach
通讯作者：
J. Rokach
复合羟基二十碳四烯酸 (HETE) 的人 PMN 白细胞趋化活性。
影响因子：
4.4
作者：
E. Goetzl;W. Pickett
通讯作者：
W. Pickett
DOI：
10.1152/ajplung.00390.2005
发表时间：
2006-04-01
影响因子：
4.9
作者：
Hurley, BP;Williams, NL;McCormick, BA
通讯作者：
McCormick, BA