A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch.
A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch.
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DOI：
10.1126/scisignal.aal5241
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发表时间：
2017-08-22
影响因子：
7.3
通讯作者：
Iadarola MJ
中科院分区：
文献类型：
--
作者：
Ramsden CE;Domenichiello AF;Yuan ZX;Sapio MR;Keyes GS;Mishra SK;Gross JR;Majchrzak-Hong S;Zamora D;Horowitz MS;Davis JM;Sorokin AV;Dey A;LaPaglia DM;Wheeler JJ;Vasko MR;Mehta NN;Mannes AJ;Iadarola MJ
慢性疼痛和瘙痒是常见的超敏反应综合征，受内源性介质的影响。我们应用了一种基于系统的翻译方法来预测、发现和表征受饮食和炎症调节的疼痛和瘙痒的介质。对组织特异性前体丰度和生物合成基因表达的分析预测，发炎皮肤中将含有四种以前未知的11-羟基-环氧亚油酸或11-酮-环氧亚油酸衍生物，以及四种先前识别的9-或13-羟基-环氧亚油酸或9-或13-酮-环氧亚油酸衍生物。质谱仪证实所有这些介体在大鼠和人的皮肤中都是丰富的。然而，只有这两种11-羟基-环氧十八烯酸盐敏化大鼠背根神经节神经元，在低pH(模拟炎症状态)或辣椒素(激活参与伤害性感受的离子通道)时，释放更多参与疼痛传递的降钙素基因相关肽(CGRP)。这两个11-羟基-环氧十八烯酸盐共用一个3-羟基-Z-戊烯基-E-环氧化物部分，因此这一亚结构可能介导了伤害感受器的敏化。在大鼠中，皮内注射11-hydroxy-12，13-trans-epoxy-(9Z)-octadecenoate可引起C纤维介导的热痛敏感性。在一项测试治疗顽固性慢性头痛的辅助策略的随机试验中，减少亚油酸的饮食摄入量与血浆11-hydroxy-12，13-trans-epoxy-(9Z)-octadecenoate，的降低有关，这与临床疼痛减轻有关。人类银屑病患者皮肤中9-酮-12，13-反式-环氧基-(10E)-十八烯酸的含量是对照皮肤的30倍，皮内注射这种化合物会引起小鼠瘙痒相关的抓挠行为。总而言之，这些发现定义了一类在疼痛和瘙痒中具有潜在作用的内源性介质。
Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy-or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene–related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z-pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber–mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy-(10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.
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影响因子：
15.9
作者：
Ji RR;Xu ZZ;Strichartz G;Serhan CN
通讯作者：
Serhan CN
影响因子：
3.3
作者：
Goswami SC;Thierry-Mieg D;Thierry-Mieg J;Mishra S;Hoon MA;Mannes AJ;Iadarola MJ
通讯作者：
Iadarola MJ
影响因子：
3.7
作者：
Kelley MR;Jiang Y;Guo C;Reed A;Meng H;Vasko MR
通讯作者：
Vasko MR
影响因子：
4.2
作者：
HANSEN, AE;HAGGARD, ME;WIESE, HF
通讯作者：
WIESE, HF
影响因子：
8.3
作者：
Goodfriend, TL;Ball, DL;Nithipatikom, K
通讯作者：
Nithipatikom, K