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The Prostaglandin E2 Stimulates Hepatocyte Growth Factor Release in Human Fetal Lung Fibroblast Cell Line through EP2 receptor and cAMP pathway

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dc.contributor.authorPark, JH-
dc.contributor.authorIwasawa, S-
dc.contributor.authorIkari, J-
dc.contributor.authorGunji, Y-
dc.contributor.authorMichalski, J-
dc.contributor.authorFarid, M-
dc.contributor.authorWang, M-
dc.contributor.authorBasma, H-
dc.contributor.authorNelson, A-
dc.contributor.authorLiu, M-
dc.contributor.authorRennard, S-
dc.description.abstractBACKGROUND: Prostaglandin E2 (PGE2) level is increased in the lower respiratory tract of patients with chronic obstructive pulmonary disease (COPD). Hepatocyte growth factor (HGF) is a fibroblast derived growth factor that plays an important role in modulating epithelial cell proliferation. In some types of mesenchymal cells, PGE2 has been reported to modulate HGF production. The current study was to determine if PGE2 modulated lung fibroblast HGF production and to determine the specific receptors involved.
METHODS: Human fetal lung fibroblasts (HFL-1) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) with 10% fetal calf serum. For stimulation, media were changed to DMEM without serum and supplemented with PGE2 or specific agonists (ONO-DI-004, ONO-AE1-259, ONO-AE-248, ONO-AE1-329) and antagonists for each of the four E-prostanoid (EP) receptors. Concentration dependence experiments were performed with PGE2 and EP2 agonist (10-6 M to 10-10 M). Media were harvested after two days and assayed for HGF by ELISA. Forskolin, and KT-5720 (PKA antagonist), were treated to determine the downstream pathway.
RESULT: Release of HGF was stimulated by PGE2 (p<0.05). The effect was greater as cells became confluent in culture over 10 days. Both PGE2 and the EP2 agonist stimulated HGF release in a concentration dependent manner. EP2 antagonist(10-5 - 10-6 M) inhibited the stimulatory effect of PGE2 and EP2 agonist. The other EP agonists and EP antagonists did not alter HGF release. Forskolin (10-5 - 10-6 M) treatment also enhanced HGF release (p<0.05). KT-5720 (10-6 M) inhibited HGF release (p<0.05).
CONCLUSION: Lung fibroblasts produce HGF and this production is stimulated by PGE2 acting on the EP2 receptor. Forskolin has a similar effect suggesting that the effect is mediated by modulation of cAMP. The pathway of HGF release through the stimulation by PGE2 is a potential target to modulate lung tissue repair and remodeling.
dc.titleThe Prostaglandin E2 Stimulates Hepatocyte Growth Factor Release in Human Fetal Lung Fibroblast Cell Line through EP2 receptor and cAMP pathwayen
dc.contributor.departmentDepartment of Pulmonary & Critical Care Medicine, Ajou University School of Medicine-
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