Epoxyeicosatrienoic acids in tissue and organ regeneration: research status and prospects

doi:10.3969/j.issn.2095-4344.1076

Abstract

Abstract:

BACKGROUND: Epoxyeicosatrienoic acids are lipid mediators produced by arachidonic acid metabolism. Early clinical studies on epoxyeicosatrienoic acids mainly focus on inflammation, pain, cardiovascular and cancer diseases. In recent years, epoxyeicosatrienoic acids have been found to be closely related to regeneration of tissues and organs in vivo and in vitro.
OBJECTIVE: To review the origin and metabolism of epoxyeicosatrienoic acids, the role of epoxyeicosatrienoic acids in the tissue and organ regeneration as well as related mechanisms associated with neovascularization and inflammation, so as to provide the basis for future research.
METHODS: CNKI and PubMed databases were searched using the keywords of “epoxyeicosatrienoic acids, tissue regeneration, organ regeneration, angiogenesis” in Chinese and English, respectively, to retrieve relevant articles published from January 2000 to February 2018. Sixty-nine representative articles were selected for overview.
RESULTS AND CONCLUSION: Epoxyeicosatrienoic acids, as important lipid molecules produced by arachidonic acid, play an important role in the growth and regeneration of tissues and organs. The related mechanisms mainly focus on the neovascularization. Tissue regeneration and repair involve the regulation of proinflammatory and anti-inflammatory cytokines. Epoxyeicosatrienoic acids have been shown to be the important signals in regulating inflammation, pain and neovascularization. Consequently, the further exploration of the relevant mechanisms of epoxyeicosatrienoic acids in tissue and organ regeneration, can provide novel treatment idea for soft tissue defects, and other defects caused by periodontitis, trauma, inflammation and tumor.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Arachidonic Acid, Regenerative Medicine, Blood Vessels, Tissue Engineering

CLC Number:

R458

Dang Haixia1, Wang Fu2. Epoxyeicosatrienoic acids in tissue and organ regeneration: research status and prospects[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(7): 1122-1128.

Figures/Tables 2

2.1 EETs的来源及代谢 EETs是花生四烯酸的代谢产物。花生四烯酸在生物体内主要是以磷脂的形式存在于细胞膜上，当细胞膜受到各种刺激时，其通过甘油二酯脂肪酶和磷脂酶A2等多种酶代谢而产生游离的花生四烯酸，而后迅速被一系列酶代谢而生成脂质介质，这一代谢过程被称为信号级联反应[8-10]。该信号级联的脂质信号在调节许多基本生物过程中发挥着很重要的作用，成为人类多种疾病重要的治疗靶点[8-10]。花生四烯酸主要有3条代谢通路：环氧合酶(Cyclooxygenase，COX)，脂氧合酶(Lipoxygenase，LOX)和细胞色素P450(Cytochrome P450，CYP)代谢途径[8]。花生四烯酸通过环氧合酶和脂氧合酶途径主要合成前列腺素和白三烯，这两类类花生酸在组织再生方面已有广泛研究[11-12]，而关于CYP衍生的类花生酸研究主要集中于炎症和心血管功能[8，13]。花生四烯酸的CYP代谢途径又分为两个分支：CYP的ω-1羟化酶(主要为CYP4A和CYP4F)催化花生四烯酸羟基化生成19-羟二十酸(19-hydroxyeicosatetraenoic acid，19-HETE)和20羟二十烷四烯酸(20-hydroxyeicosatetraenoic acid，20-HETE)。其中，20-HETE被研究证实可诱发高血压、内皮功能障碍、炎症、心血管疾病、血管生成和肿瘤成长[14-17]。CYP途径的另一个分支，即CYP表氧化酶(主要是CYP2C和CYP2J)催化花生四烯酸环氧化生成EETs，其包括4种异构体，即5，6-EET，8，9-EET，11，12-EET和14，15-EET[5]。EETs的生物活性较高，但其在体内高度不稳定，在体内合成后即迅速被可溶性环氧化物水解酶(soluble epoxide hydrolase，sEH，由EPHX2编码) 水解生成相对应的生理活性较低的双羟基二十碳四烯酸(dihydroxyeicosatrienoic acids，DHETs)，相应的4种异构体为：5，6-DHET、8，9-DHET、11，12-DHET和14，15-DHET(见图1)。当前，通过靶向阻断sEH而提高内源性EETs成为主要研究手段。在过去的10多年，人们对于sEH的抑制剂(soluble epoxide hydrolase inhibitor，sEHi)进行了大量的研发，从早期的环氧类sEHi已开发到第3代脲类sEHi，sEHi在体内应用和临床试验中得到了快速的发展[18-21]。"

2.2 EETs促进组织和器官的生长及再生 2.2.1 EETs促进组织生长研究显示，EETs具有促进胰岛增大和轴突生长的功能。Luria等[22]发现EETs可增加胰岛的大小并可改进胰岛素的信号和灵敏度。该研究组通过基因敲除编码sEH的基因EPHX2以及外源性给予sEHi研究发现，与野生型小鼠相比，实验组小鼠胰岛明显增大，胰腺组织学切片发现新生血管明显增多。此外，有研究者通过体外研究发现，EETs还具有促进轴突生长的功能[3]。该研究组运用大脑皮质、交感神经、感觉神经原代神经元细胞培养物，通过免疫反应证实sEH位于神经元的轴突，通过添加外源性EETs以及sEHi发现，与对照组相比，实验组神经元细胞轴突长度明显增长。 2.2.2 EETs促进组织和器官再生近些年研究表明，EETs具有促进伤口愈合、颅骨缺损区骨组织再生、角膜新生血管、新生视网膜血管形成及器官再生等功能[2，4-5]。有研究者通过体外实验在小鼠耳背部创建标准化的全层皮肤缺损创面，发现EETs可明显促进伤口处上皮和血管新生，并研究得出该作用可能是通过SDF1α和血管内皮生长因子(vascular endothelia growth factor，VEGF)协同上调实现的[4]。在骨组织再生方面，利用C57BL/6小鼠颅骨缺损模型，发现14，15-EET处理侧新生骨量、血管内皮生长因子表达和新生血管数较对照侧明显增多，提示14，15-EET促进颅骨缺损区骨组织再生可能与其改善局部微循环有关[2]。这些研究结果可能为牙周病、创伤、炎症和肿瘤等造成的骨缺损疾病提供一种新的治疗思路。此外，2013年Panigrahya等[5]，发现EETs可明显促进伤口愈合、角膜新生血管和视网膜血管的形成。通过基因学和药理学手段控制内源性EETs水平发现EETs在促进器官再生中也发挥了关键的作用，能够促进肝再生，肾和肺代偿性生长。这些研究结果为评估EETs或sEHi对人类多种疾病作为新的治疗靶点提供了线索，可望用于肝损伤或手术切除后的肝功能不全的组织再生。此外，鉴于EETs具有促进肺代偿性生长的作用，EETs或其代谢酶抑制剂sEHi可能对肺发育不良具有一定的治疗效果，如支气管肺发育不良[5]。 2.3 EETs促进组织再生的机制研究见表1。"

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