Prostaglandin E_2 inhibits airway inflammation

为探讨前列腺素E_2受体在呼吸道炎症中黏液高分泌中的作用，我们通过鼻内滴注脂多糖(LPS)和OVA致敏大鼠鼻腔内注入卵清蛋白(OVA)诱导了大鼠鼻上皮杯状细胞的肥大和化生改变。皮下注射EP-4激动剂(ONO-AE1329，1~100μg/kg体重)可剂量依赖性地抑制内毒素诱导的黏液生成和中性粒细胞的浸润。EP-4激动剂也能显著抑制卵子诱导的粘液产生，但不影响嗜酸性粒细胞的浸润。鼻腔注射EP-4激动剂和OVA激发(3次)可显著抑制粘液的产生，而注射EP-4和OVA致敏(4次)对黏液产生无明显影响。EP3激动剂(ONO-AE-248,100μg/kg)也能抑制内毒素诱导的黏液产生，而EP-1激动剂(ONO-DI-004)和EP-2激动剂(ONO-AE1259-01)则无此作用。用抗粘蛋白单抗(抗MUC5AC和HCS18)用酶联免疫吸附试验检测粘液分泌。EP1、EP2、EP3和EP4激动剂可显著抑制内毒素诱导的黏液分泌，而EP3和EP4激动剂可抑制内毒素诱导的IL-8分泌。自发性和脂多糖诱导的IL-6和GM-CSF的分泌不受影响。这些结果表明前列腺素E_2通过EP受体抑制内毒素刺激引起的粘液高分泌和变态反应性炎症。

To examine the function of prostaglandin E_2 receptors on mucus hypersecretion in airway inflammation, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of lipopolysaccharides(LPS), and by intranasal ovalbumin(OVA) instillation in OVA-sensitized rats. Subcutaneous injection of EP-4 agonist (ONO-AE1-329,1-100 μg/kg weight) dose-dependently inhibited LPS-induced mucus production and neutrophil infiltration. OVA-induced mucus production was also significantly inhibited by EP-4 agonist, however, eosinophil infiltration was not affected. Simultaneous injection of EP-4 agonist with intranasal OVA challenge (three instillations) significantly inhibited mucus production, but EP-4 injection with intraperitoneal OVA sensitization (four injections) did not. EP3 agonist (ONO-AE-248,100 μg/kg) also inhibited LPS-induced mucus production, whereas EP-1 agonist (ONO-DI-004) and EP-2 agonist (ONO-AE1-259-01) showed no effect.In vitro effects of EP agonists on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using anti-mucin monoclonal antibodies (anti-MUC5AC and HCS18). Spontaneous mucus secretion and IL-8 secretion were not affected by EP agonists, however, LPS-induced mucus secretion was significantly inhibited by EP1,EP2,EP3,and EP4 agonists at 10^<-6>M, and LPS-induced IL-8 secretion was inhibited by EP3,and EP4 agonists. Spontaneous and LPS-induced IL-6 and GM-CSF secretion were not affected. These results indicate that prostaglandin E_2 inhibits mucus hypersecretion caused by LPS stimulation and allergic inflammation through the EP receptors/