Investigation of the mechanism of Rho-mediated pulmonary vascular permeability enhancement using bortezomib.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17652
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nippon Medical School
• Principal Investigator: Kashiwada Takeru 日本医科大学, 医学部, 講師 (50754991)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 薬剤性肺障害 / ボルテゾミブ / Rho

Outline of Final Research Achievements

Bortezomib (BTZ), a selective 26S proteasome inhibitor, has clinical utility in multiple myeloma and mantle cell lymphoma. Prior to approval of treatment, several pulmonary complications were reported with BTZ, including capillary leak syndrome of the vascular hyperpermeability type, the frequency of which has decreased markedly in recent years with the use of steroids. In this study, we investigated the mechanism by which BTZ increases endothelial cell permeability. BTZ increased Rho protein in vascular endothelial cells, resulting in stress fiber formation via the Rho/ROCK pathway and enhanced vascular permeability in a Rho-dependent manner. We also found that stress fiber formation by BTZ has additive effects with inflammatory cytokines. This suggests that BTZ may accumulate Rho in endothelial cells, amplifying the active GTP-bound state of RhoA due to inflammation and increasing vascular permeability.

Free Research Field

呼吸器疾患

Academic Significance and Societal Importance of the Research Achievements

本検討は、ボルテゾミブによる肺障害発症機序の分子メカニズムを検討した初めての報告である。我々は、ボルテゾミブが内皮細胞中にRhoの蓄積を来し、Rho依存的透過性亢進を惹起し、肺障害を来すことを見出した。この結果は、Rho依存的な透過性亢進が薬剤性肺障害を含む間質性肺炎の発症機序となりえる可能性を示唆する。プロテアソーム阻害剤の機能や、肺炎を含む内皮細胞炎症の病態解明において、新たな視点をもたらすと考える。