Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-β1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-β1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-β1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.

环氧二十碳三烯酸 (EET) 是花生四烯酸的代谢物，可通过可溶性环氧化物水解酶 (sEH) 快速代谢成二醇。已显示抑制 sEH 可增加 EET 的生物活性，已知 EET 具有抗炎特性。然而，EET 在肺纤维化中的作用仍未得到探索。液相色谱和串联质谱 (LC-MS/MS) 用于分析特发性肺纤维化 (IPF, n  = 29) 和对照组 ( n = 15)，并在体外和体内肺纤维化模型中评估了 11,12-EET 的功能。IPF 肺组织中的 EET 水平，包括 8,9-EET、11,12-EET 和 14,15-EET，显着低于对照组织。人肺组织中的 11,12-EET/11,12-DHET 比率也将 IPF 与对照组织区分开来。11,12-EET 显着降低了 IPF 患者 MRC-5 细胞和原代成纤维细胞中转化生长因子 (TGF)-β1 诱导的 α-平滑肌肌动蛋白 (SMA) 和 I 型胶原的表达。sEH 特异性 siRNA 和 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) 脲（TPPU；sEH 抑制剂）也降低了 TGF-β1 诱导的成纤维细胞中 α-SMA 和 I 型胶原蛋白的表达。此外，11，12-EET 和 TPPU 降低了 IPF 患者原代成纤维细胞中 TGF-β1 诱导的 p-Smad2/3 和细胞外信号调节激酶 (ERK) 表达和 Beas-2B 细胞中纤连蛋白的表达。TPPU 降低了博莱霉素诱导小鼠肺中羟脯氨酸的水平。11,12-EET 或 sEH 抑制剂可以通过调节 TGF-β1 诱导的促纤维化信号传导来抑制肺纤维化，这表明 11,12-EET 和 EET 的调节可以作为 IPF 治疗的潜在治疗靶点。