Conners M S, Schwartzman M L, Quan X, Heilman E, Chauhan K, Falck J R, Godfrey H P
Department of Pharmacology, New York Medical College, Valhalla 10595.
J Invest Dermatol. 1995 Jan;104(1):47-51. doi: 10.1111/1523-1747.ep12613482.
Delayed-type hypersensitivity (DTH) reactions are initiated by sensitized T cells. Their progression is dependent upon the local release of various autacoids, including cytokines and eicosanoids, by T cells, infiltrating inflammatory cells, and resident tissue cells. 12(R)-hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE], an eicosanoid produced by skin and cornea, possesses potent proinflammatory properties at picomolar concentrations including vasodilation, increase in membrane permeability, neutrophil chemotaxis, and angiogenesis. Because DTH reactions are associated with many of these same phenomena, we examined the effect of 12(R)-HETrE and related 12-hydroxyeicosanoids on the expression of DTH to purified protein derivative of tuberculin in sensitized guinea pigs. In the absence of purified protein derivative of tuberculin, none of the eicosanoids evoked erythema or edema after intradermal injection at doses up to 100 pmol. When injected together with purified protein derivative of tuberculin, 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(R)-HETE], but not its enantiomer 12(S)-HETE, significantly inhibited macroscopic expression of delayed reactivity (erythema) only at the highest dose tested, 10 pmol. In contrast, 12(R)-HETrE significantly enhanced expression of DTH at doses between 1 fmol and 1 pmol (50% and 30% increases above control, respectively). Its stereoisomer, 12(S)-HETrE, did not enhance DTH at any tested dose, but was able to block the activity of 12(R)-HETrE when injected simultaneously. Enhancement or inhibition of visible skin responses was not associated with qualitative or quantitative changes in cellular infiltrates at the reaction site. 12(R)-HETrE had no effect on the nonimmunologic inflammatory skin reaction induced by phorbol myristate acetate, suggesting selectivity toward DTH. We conclude that 12(R)-HETrE enhances DTH via a yet to be determined mechanism and that its stereoisomer, 12(S)-HETrE, may be a useful antagonist for studying the inflammatory actions of this eicosanoid.
迟发型超敏反应（DTH）由致敏T细胞引发。其进展取决于T细胞、浸润性炎症细胞和组织驻留细胞在局部释放的多种自分泌物质，包括细胞因子和类花生酸。12（R）-羟基-5,8,14-二十碳三烯酸[12（R）-HETrE]是一种由皮肤和角膜产生的类花生酸，在皮摩尔浓度下具有强大的促炎特性，包括血管舒张、膜通透性增加、中性粒细胞趋化性和血管生成。由于DTH反应与许多相同的现象相关，我们研究了12（R）-HETrE和相关的12-羟基类花生酸对致敏豚鼠结核菌素纯蛋白衍生物迟发型超敏反应表达的影响。在没有结核菌素纯蛋白衍生物的情况下，在高达100皮摩尔的剂量下进行皮内注射时，没有一种类花生酸能引起红斑或水肿。当与结核菌素纯蛋白衍生物一起注射时，12（R）-羟基-5,8,10,14-二十碳四烯酸[12（R）-HETE]，而不是其对映体12（S）-HETE，仅在最高测试剂量10皮摩尔时显著抑制迟发型反应（红斑）的宏观表现。相比之下，12（R）-HETrE在1飞摩尔至1皮摩尔的剂量下显著增强了DTH的表达（分别比对照增加50%和30%）。其立体异构体12（S）-HETrE在任何测试剂量下均未增强DTH，但在同时注射时能够阻断12（R）-HETrE的活性。可见皮肤反应的增强或抑制与反应部位细胞浸润的定性或定量变化无关。12（R）-HETrE对佛波酯诱导的非免疫性炎症皮肤反应没有影响，表明其对DTH具有选择性。我们得出结论，12（R）-HETrE通过一种尚未确定的机制增强DTH，并且其立体异构体12（S）-HETrE可能是研究这种类花生酸炎症作用的有用拮抗剂。
