Effects of Subtype-selective E Prostanoid Receptor Agonists on Bleomycin-induced Pulmonary Fibrosis in Rats

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  • ICHIYAMA Takashi
    First Department of Internal Medicine, Shinshu University School of Medicine
  • YAMAMOTO Hiroshi
    First Department of Internal Medicine, Shinshu University School of Medicine
  • HONGO Kazuhiro
    Department of Drug Discovery Science, Shinshu University School of Medicine

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Background : Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited treatment options and a poor prognosis. In vitro research has shown that prostaglandin (PG) E2 can suppress pulmonary fibrosis via cAMP production. EP2 and EP4, which are subtypes of the receptors for PGE2, are involved in cAMP production. The present study was designed to examine the effects of EP2 and EP4 agonists on bleomycin (BLM)-induced pulmonary fibrosis in rats.<br>Materials and Methods : The EP2 and EP4 agonists were subcutaneously administered to BLM-induced pulmonary fibrosis rats for 21 days. The lung weight, mRNA expressions of transforming growth factor (TGF)-β1 and procollagen genes, and degree of pulmonary fibrosis were compared between EP2 agonist, EP4 agonist, vehicle, and pirfenidone and nintedanib administered groups. We also examined the EP2 and EP4 expressions in human lung tissues with IPF and in rat lung tissues with BLM-induced pulmonary fibrosis by immunohistochemical staining. The human lung tissues with IPF were obtained from autopsy cases.<br>Results : The EP2 agonist significantly suppressed the lung weight gain and inhibited the mRNA expressions of TGF-β1 and procollagen genes. In addition, the fibrosis scores and hydroxyproline content tended to be lower in the EP2 agonist administered group. However, the EP4 agonist did not show such evidence in suppression of fibrosis. The enhanced expressions of EP2 and EP4 were demonstrated in both human and rat lung tissues with fibrosis relative to those in normal lung.<br>Conclusions : The EP2 agonist may become a novel therapeutic agent for IPF.

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