Investigation of involvement of hypoxia-inducible factor 1 on cigarette smoke-induced airway and lung pathological events

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10974
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Kansai Medical University
• Principal Investigator: NISHI Kenichiro 関西医科大学, 医学部, 研究員 (50340716)
• Co-Investigator(Kenkyū-buntansha): 広田 喜一 関西医科大学, 医学部, 教授 (00283606)
• Research Collaborator: MATSUO Yoshiyuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: タバコ / HIF-1 / 低酸素誘導性因子1 / 酸素代謝 / 慢性閉塞性肺疾患 / 活性酸素

Outline of Final Research Achievements

Cigarette smoke (CS) is a major contributor to the development of a large number of fatal and debilitating disorders. However, the precise molecular mechanisms underlying the effects of CS in lung disease are largely unknown. To elucidate these pathophysiological processes, we examined the n vitro and in vivo effects of CS extract (CSE) and CS on the transcription factor, hypoxia-inducible factor 1 (HIF-1). CSE induced concentration- and time-dependent accumulation of HIF-1α protein in human lung epithelial-like cells under non-hypoxic conditions. Further investigation revealed that reactive oxygen species were generated in cells exposed to CSE and were required for CSE-mediated induction of HIF-1α protein, as was activation of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. In conclusion, we demonstrated that CSE and CS induced HIF-1 activation in vitro and in vivo, respectively.

Free Research Field

麻酔科学

Academic Significance and Societal Importance of the Research Achievements

生体の低酸素応答研究の流れに沿った本申請の研究は、細胞内に内在する酸素分圧感知機構とその下流の転写因子、HIF-1の機能と喫煙が生体にもたらす影響を関連づけて解析するという従来にはなかった観点を持ち新規性を有している。このような周術期合併症との関連に加えて慢性的なタバコへの暴露が肺胞上皮機能の機能のみならず肺の解剖学的な再構築を経た肺線維症にいたる過程も視野に収めた研究成果が得られた。