5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling
5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling
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DOI：
10.1096/fj.201903207rrr
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发表时间：
2021-04-01
期刊：
影响因子：
4.8
通讯作者：
Murata, Takahisa
中科院分区：
文献类型：
--
作者：
Kobayashi, Koji;Ashina, Kohei;Murata, Takahisa
5,6-二羟基-8Z,11Z,14Z,17Z-二十碳四烯酸 (5,6-DiHETE) 是一种二十碳五烯酸衍生的脂质代谢物，我们之前在发炎的小鼠结肠中检测到。在本研究中，我们研究了 5,6-DiHETE 在小鼠结肠炎中的病理生理作用及其潜在作用机制，重点关注对瞬时受体电位香草酸 (TRPV) 通道活性的影响。口服右旋糖酐硫酸钠（DSS，2%，持续4天）引起结肠炎症，在第7天达到高峰，并在第18天逐渐下降。结肠组织中5,6-DiHETE浓度在结肠炎愈合阶段（第9至18天）显着增加。体外研究表明，用 5,6-DiHETE（0.1-1 μM，30 分钟）预处理可显着抑制 TRPV4 激动剂（GSK1016790A，50 nM）诱导的内皮屏障破坏。细胞内 Ca2+ 成像还显示，在过表达 TRPV4 的 HEK293T 细胞中，用 5,6-DiHETE（1 μM，10 分钟）预处理可减少 GSK1016790A 诱导的细胞内 Ca2+ 增加。在体内，在愈合阶段腹膜内施用5,6-DiHETE（50μg·kg(-1)·天(-1)）加速了DSS诱导的结肠炎的恢复。病理学研究表明，给予5,6-DiHETE可抑制发炎结肠组织中的水肿形成和白细胞浸润。总之，我们确定 5,6-DiHETE 是一种新型内源性 TRPV4 拮抗剂，并且我们还证明其给药通过抑制炎症反应来促进结肠炎的愈合。
5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6-DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4 days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6-DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6-DiHETE (0.1-1 mu M, 30 minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50 nM). Intracellular Ca2+ imaging also showed that pretreatment with 5,6-DiHETE (1 mu M, 10 minutes) reduced GSK1016790A-induced intracellular Ca2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6-DiHETE (50 mu g kg(-1) day(-1)) during the healing phase accelerated the recovery from DSS-induced colitis. Pathological studies showed that the administration of 5,6-DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6-DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.