Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice.
Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice.
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DOI：
10.1007/s00441-015-2262-0
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发表时间：
2016-02
影响因子：
3.6
通讯作者：
Guan CX
中科院分区：
文献类型：
--
作者：
Zhou Y;Yang J;Sun GY;Liu T;Duan JX;Zhou HF;Lee KS;Hammock BD;Fang X;Jiang JX;Guan CX
环氧二十碳三烯酸（EETs）是花生四烯酸经细胞色素P450（CYP450）环氧化酶代谢产生的产物，主要由可溶性环氧化物水解酶（sEH）代谢为相应的二醇。EETs而非其二醇具有抗炎特性，抑制sEH可能对炎症性纤维化产生保护作用。在本研究中，我们测试了一种选定的sEH抑制剂——1 - 三氟甲氧基苯基 - 3 -（1 - 丙酰基哌啶 - 4 - 基）脲（TPPU）对博来霉素诱导的小鼠肺纤维化（PF）的影响。通过气管内注射博来霉素建立小鼠肺纤维化模型，在博来霉素注射后给予TPPU治疗21天。我们发现TPPU治疗改善了博来霉素刺激小鼠的体重减轻情况和存活率。组织学检查显示，TPPU治疗减轻了博来霉素诱导的炎症，并维持了肺组织的肺泡结构。TPPU还减少了博来霉素诱导的小鼠肺组织中胶原蛋白的沉积以及Ⅰ型前胶原mRNA的表达。TPPU降低了博来霉素刺激小鼠血清中转化生长因子 - β1（TGF - β1）、白细胞介素 - 1β（IL - 1β）和白细胞介素 - 6（IL - 6）的水平。此外，TPPU抑制了小鼠成纤维细胞的增殖和胶原蛋白合成，并部分逆转了转化生长因子 - β1诱导的α - 平滑肌肌动蛋白（α - SMA）表达。我们的研究结果表明，抑制sEH可减轻博来霉素诱导的炎症和胶原蛋白沉积，从而预防博来霉素诱导的小鼠肺纤维化模型的发生。
Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs, but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory fibrosis. In this study, we tested the effects of a selected sEH inhibitor, 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea (TPPU), on bleomycin-induced pulmonary fibrosis (PF) in mice. A mouse model of PF was established by intratracheal injection of bleomycin, and TPPU was administered for 21 days after bleomycin injection. We found TPPU treatment improved the body weight loss and survival rate of bleomycin-stimulated mice. Histological examinations showed that TPPU treatment alleviated bleomycin-induced inflammation, and maintained alveolar structure of pulmonary tissues. TPPU also decreased bleomycin-induced deposition of collagen, and expression of the procollagen I mRNA in lung tissues of mice. TPPU decreased the TGF-β1, IL-1β and IL-6 levels in serum of bleomycin-stimulated mice. Moreover, TPPU inhibited proliferation, collagen synthesis of the mouse fibroblasts, and partially reversed TGF-β1-induced α-SMA expression. Our results indicated that inhibition of sEH attenuates bleomycin-induced inflammation, collagen deposition, and therefore prevents bleomycin-induced PF in mice model.