Platelet-activating factor (PAF), a bioactive ether phospholipid with significant pro-inflammatory properties, was identified almost half a century ago. Despite extensive study of this autocoid, therapeutic strategies for targeting its signaling components have not been successful, including the recent clinical trials with darapladib, a drug that targets plasma PAF-acetylhydrolase (PAF-AH). We recently provided experimental evidence that the previously unrecognized acyl analog of PAF, which is concomitantly produced along with PAF during biosynthesis, dampens PAF signaling by acting both as a sacrificial substrate for PAF-AH and probably as an endogenous PAF-receptor antagonist/partial agonist. If this is the scenario in vivo, PAF-AH needs to catalyze the selective hydrolysis of alkyl-PAF and not acyl-PAF. Accordingly, different approaches are needed for treating inflammatory diseases in which PAF signaling is implicated. The interplay between acyl-PAF, alkyl-PAF, PAF-AH, and PAF-R is complex, and the outcome of this interplay has not been previously appreciated. In this review, we discuss this interaction based on our recent findings. It is very likely that the relative abundance of acyl and alkyl-PAF and their interactions with PAF-R in the presence of their hydrolyzing enzyme PAF-AH may exert a modulatory effect on PAF signaling during inflammation.

血小板活化因子 (PAF) 是一种具有显着促炎特性的生物活性醚磷脂，几乎在半个世纪前就被发现了。尽管对这种自体进行了广泛的研究，但针对其信号成分的治疗策略尚未成功，包括最近使用 darapladib 进行的临床试验，这是一种靶向血浆 PAF-乙酰水解酶 (PAF-AH) 的药物。我们最近提供的实验证据表明，先前未被识别的 PAF 酰基类似物，在生物合成过程中与 PAF 一起产生，通过充当 PAF-AH 的牺牲底物和可能作为内源性 PAF 受体拮抗剂/部分激动剂来抑制 PAF 信号传导. 如果是vivo的场景，PAF-AH 需要催化烷基-PAF 而不是酰基-PAF 的选择性水解。因此，需要不同的方法来治疗涉及 PAF 信号传导的炎性疾病。酰基-PAF、烷基-PAF、PAF-AH 和 PAF-R 之间的相互作用是复杂的，这种相互作用的结果以前没有被认识到。在这篇综述中，我们根据我们最近的发现讨论了这种相互作用。很可能酰基和烷基-PAF 的相对丰度以及它们在水解酶 PAF-AH 存在下与 PAF-R 的相互作用可能对炎症过程中的 PAF 信号传导产生调节作用。