|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 2004 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 2003 : ¥1,500,000 (Direct Cost : ¥1,500,000)
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/