Differential cytotoxicity induced by statins in inflammatory mileaus

2022 Fiscal Year Final Research Report

• Project/Area Number: 17K11072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Teikyo University (2018-2022); The University of Tokyo (2017)
• Principal Investigator: Chang Kyungho 帝京大学, 医学部, 教授 (50302708)
• Co-Investigator(Kenkyū-buntansha): 山田 芳嗣 国際医療福祉大学, 国際医療福祉大学三田病院, 教授 (30166748)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Keywords: 急性呼吸促迫症候群 / ARDS / デキサメサゾン / 炎症性サイトカイン / スタチン / アポトーシス / JNK / AKT

Outline of Final Research Achievements

Although pharmacological interventions have long been tried for resolution of ARDS, the results are far from satisfactory. We set an ARDS-simulating in-vitro model, where typical inflammatory cytokines are added in human alveolar epithelial cell-derived A549 cell culture, and searched for agents with cytoprotective property in this milieu. In this system, statins, irrespective of their hydrophilicity, did not show cytoprotection, but cytotoxicity. While, dexamethasone and rapamycin exerted significant cytoprotective effects through JNK inhibition and AKT activation. Especially, co-administration of both agents showed remarkable synergistic cytoprotective effect. This result gave a basic rationale for efficacy of dexamethasone and other anti-inflammatory agents on severe covid-19 pneumonia in the situation of the novel coronavirus pandemic.

Free Research Field

集中治療医学

Academic Significance and Societal Importance of the Research Achievements

急性肺障害に対する抗炎症薬のin vitroでの保護効果としては、残念ながらスタチンの効果は認めなかったが、グルココルチコイドでの保護効果、抗炎症薬の共投与での相乗作用及び、その分子的機序の一旦を明らかにできた。奇しくも、この３年間の新型コロナウィルスパンデミックにおける、covid-19重症肺炎でステロイドが有効なこと、他の抗炎症薬との共投与に意味があることに基礎研究上の裏付けを与えることができたので、今後とも学会発表及び論文公表で発信を行っていきたい。