Role of prostaglandin transporter in pulmonary fibrosis and its therapeutic significance

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H04755
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kanazawa University
• Principal Investigator: Nakanishi Takeo 金沢大学, 薬学系, 准教授 (30541742)
• Co-Investigator(Kenkyū-buntansha): 小森 久和 金沢大学, 薬学系, 助教 (00634180)
• Research Collaborator: Wakayama Tomohiko ; Deguchi Yoshiharu ; Hinoi Eiichi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: トランスポーター / 肺 / 線維化 / プロスタグランジン / 炎症 / OATP2A1/SLCO2A1

Outline of Final Research Achievements

Expression of functional prostaglandin transporter (OATP2A1/SLCO2A1) responsible for local distribution of an inflammatory mediator, prostaglandin E2 (PGE2), was investigated in the lungs using animal and cellular models for pulmonary fibrosis. Oatp2a1 was found to be expressed at the apical membranes of type 1 alveolar epithelial cells (AT1) in the mouse lungs, and to mediate transcellular transport of PGE2 from alveolar lumen to interstitial tissues. In a bleomycin-induced pulmonary fibrosis model, PGE2 was accumulated in the alveolar cavity and interstitial pneumonia was aggravated in Slco2a1-/- mice, indicating an essential role of OATP2A1 in the lung homeostasis. Furthermore, several small compounds including cigarette smoke extracts were fund to alter OATP2A1 function based on in vitro screening. These findings are useful to develop a therapeutic strategy to prevent the lungs from severe inflammation and fibrosis.

Free Research Field

薬物動態学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

プロスタグランジンE2の分布を調整するプロスタグランジン輸送体（OATP2A1/SLCO2A1）の機能喪失が間質性肺炎の増悪と関連することが初めて明らかになり、OATP2A1機能が肺の恒常性維持に重要であることが示された。また、本輸送体の機能を調節する低分子化合物やその構造的特徴に関する情報も得られた。間質性肺炎は予後が極めて不良である難治性疾患であり、早急な確立が望まれている。本研究成果は、OATP2A1の機能賦活化が肺組織線維化の予防に有効であることに理論的根拠を与えるものであり、将来、間質性肺炎の治療戦略確立に向けて応用展開が期待される