13051Shiga University of Medical Science, Otsu, Shiga, Japan.
Am J Rhinol Allergy. 2022 Jan;36(1):106-114. doi: 10.1177/19458924211027682. Epub 2021 Jul 8.
17,18-Epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary oil in the gut, and antiinflammatory activity of 17,18-EpETE was recently reported.
To evaluate the inhibitory effects of 17,18-EpETE in airway inflammation, we examined in vitro and in vivo effects on mucus production, neutrophil infiltration, and cytokine/chemokine production in airway epithelium.
Nasal tissue localization of G protein-coupled receptor 40 (GPR40), a receptor of 17,18-EpETE, was determined by immunohistochemical staining. Expression of GPR40 mRNA in nasal mucosa of chronic rhinosinusitis (CRS) patients and control subjects was determined by reverse transcription-polymerase chain reaction (RT-PCR). The in vitro effects on airway epithelial cells were examined using normal human bronchial epithelial cells and NCI-H292 cells. To examine the in vivo effects of 17,18-EpETE on airway inflammation, we induced goblet cell metaplasia, mucus production, and neutrophil infiltration in mouse nasal epithelium by intranasal lipopolysaccharide (LPS) instillation.
GPR40 is mainly expressed in human nasal epithelial cells and submucosal gland cells. RT-PCR analysis revealed that the expression of GPR40 mRNA was increased in nasal tissues from CRS patients compared with those from control subjects. 17,18-EpETE significantly inhibited tumor necrosis factor (TNF)-α-induced production of interleukin (IL)-6 , IL-8, and mucin from cultured human airway epithelial cells dose dependently, and these antiinflammatory effects on cytokine production were abolished by GW1100, a selective GPR40 antagonist. Intraperitoneal injection or intranasal instillation of 17,18-EpETE significantly attenuated LPS-induced mucus production and neutrophil infiltration in mouse nasal epithelium. Inflammatory cytokine/chemokine production in lung tissues and bronchoalveolar lavage fluids was also inhibited.
These results indicate that 17,18-EpETE plays a regulatory role in mucus hypersecretion and neutrophil infiltration in nasal inflammation. Local or systemic administration may provide a new therapeutic approach for the treatment of intractable airway disease such as CRS.
17,18-环氧二十碳四烯酸（17,18-EpETE）是一种来自肠道膳食油的二十碳五烯酸代谢物，具有抗炎活性。
为评估 17,18-EpETE 在气道炎症中的抑制作用，我们检测了其在气道上皮细胞中对黏液产生、嗜中性粒细胞浸润和细胞因子/趋化因子产生的体外和体内作用。
通过免疫组织化学染色确定 G 蛋白偶联受体 40（GPR40）在鼻组织中的定位，GPR40 是 17,18-EpETE 的受体。通过逆转录聚合酶链反应（RT-PCR）确定慢性鼻-鼻窦炎（CRS）患者和对照受试者鼻黏膜中 GPR40mRNA 的表达。在体外使用正常人支气管上皮细胞和 NCI-H292 细胞检测气道上皮细胞的作用。为了检测 17,18-EpETE 对气道炎症的体内作用，我们通过鼻内给予脂多糖（LPS）诱导小鼠鼻上皮细胞的杯状细胞化生、黏液产生和嗜中性粒细胞浸润。
GPR40 主要表达于人鼻上皮细胞和黏膜下腺细胞。RT-PCR 分析显示，与对照受试者相比，CRS 患者的鼻组织中 GPR40mRNA 的表达增加。17,18-EpETE 显著抑制肿瘤坏死因子（TNF）-α诱导的培养人气道上皮细胞中白细胞介素（IL）-6、IL-8 和粘蛋白的产生，并且这些细胞因子产生的抗炎作用被选择性 GPR40 拮抗剂 GW1100 所阻断。17,18-EpETE 的腹腔内注射或鼻内给药显著减轻了 LPS 诱导的小鼠鼻上皮细胞中黏液产生和嗜中性粒细胞浸润。肺部组织和支气管肺泡灌洗液中的炎症细胞因子/趋化因子产生也受到抑制。
这些结果表明 17,18-EpETE 在鼻炎症中的黏液过度分泌和嗜中性粒细胞浸润中发挥调节作用。局部或全身给药可能为治疗慢性气道疾病（如 CRS）提供一种新的治疗方法。
