Airway remodeling consists of the structural changes of airway walls, which is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the need for early and specific therapeutic interventions. The arachidonic acid cytochrome P-450 (CYP) pathway has thus far received relatively little attention in its relation to asthma. In this study, we studied the inhibition of soluble epoxide hydrolase (sEH) on airway remodeling and hyperresponsiveness (AHR) in a chronic asthmatic model which long-term exposure to antigen over a period of 12 weeks. The expression of sEH and CYP2J2, the level of 14, 15-epoxyeicosatrienoic acids (EETs), airway remodeling, hyperresponsiveness and inflammation were analyzed to determine the inhibition of sEH. The intragastric administration of 3 or 10 mg/kg ZDHXB-101, which is a structural derivative of natural product honokiol and a novel soluble epoxide hydrolase (sEH) inhibitor, daily for 9 weeks significantly increased the level of 14, 15-EETs by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. ZDHXB-101 reduced the expression of remodeling-related markers such as interleukin (IL)-13, IL-17, MMP-9 N-cadherin, α-smooth muscle actin, S100A4, Twist, goblet cell metaplasia, and collagen deposition in the lung tissue or in bronchoalveolar lavage fluid. Moreover, ZDHXB-101 alleviated AHR, which is an indicator that is used to evaluate the airway remodeling function. The inhibitory effects of ZDHXB-101 were demonstrated to be related to its direct inhibition of the extracellular signal-regulated kinase (Erk1/2) phosphorylation, as well as inhibition of c-Jun N-terminal kinases (JNK) and the signal transducer and activator of transcription-3 (STAT3) signal transduction. These findings first revealed the anti-remodeling potential of ZDHXB-101 lead in chronic airway disease.

中文翻译：

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ZDHXB-101（3'，5-Diallyl-2，4'-dihydroxy- [1,1'-biphen-yl] -3,5'-dicarbaldehyde）通过抑制有丝分裂原的激活来防止气道重塑和反应过度激活的蛋白激酶以及转录3信号通路的信号转导和激活剂。

气道重塑由气道壁的结构变化组成，这通常被认为是长期的气道炎症的结果，但在哮喘患儿的气道中可能存在同等程度的变化，因此需要早期和具体的治疗干预。迄今为止，花生四烯酸细胞色素P-450（CYP）途径在与哮喘的关系中很少受到关注。在这项研究中，我们研究了在慢性哮喘模型中对可溶性环氧化物水解酶（sEH）的气道重塑和高反应性（AHR）的抑制作用，该模型长期暴露于抗原长达12周。分析sEH和CYP2J2的表达，14、15-环氧二十碳三烯酸（EET）的水平，气道重塑，高反应性和炎症，以确定sEH的抑制作用。每天3或10 mg / kg的ZDHXB-101胃内给药是天然产物厚朴酚和新型可溶性环氧化物水解酶（sEH）抑制剂的结构衍生物，每天持续9周可通过抑制抑制作用显着增加14、15-EET sEH的表达和CYP2J2在肺组织中的表达增加。ZDHXB-101降低了与重塑相关的标志物的表达，例如白介素（IL）-13，IL-17，MMP-9 N-钙粘蛋白，α平滑肌肌动蛋白，S100A4，Twist，杯状细胞化生和胶原沉积。肺组织或支气管肺泡灌洗液中。此外，ZDHXB-101减轻了AHR，这是用于评估气道重塑功能的指标。已证明ZDHXB-101的抑制作用与其直接抑制细胞外信号调节激酶（Erk1 / 2）磷酸化以及抑制c-Jun N端激酶（JNK）和信号转导子有关。转录3激活子（STAT3）信号转导。这些发现首先揭示了ZDHXB-101铅在慢性气道疾病中的抗重塑潜力。