Association of thrombomodulin with DAMPs suppression and improvement of organ damage in sepsis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18331
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Akatsuka Masayuki 札幌医科大学, 医学部, 助教 (60808161)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 敗血症 / ラット / DAMPs / リコンビナントトロンボモジュリン / 腎障害

Outline of Final Research Achievements

We found that Histone H3 increased with time in sepsis-induced rats. Histopathological findings showed that renal injury occurred with increasing histone H3 levels. Next, administration of three types of thrombomodulins (lectin-like domain + EGF-like domain, lectin-like domain, and EGF-like domain) suppressed histoneH3 levels and improved renal injury. In addition, thrombomodulin treatment resulted in prolonged 24-hour survival compared to the non-treated group.
The results suggest that elevated blood levels of histone H3 in sepsis are associated with renal injury, and that thrombomodulin suppresses histone proteins and reduces renal damage.

Free Research Field

敗血症、多臓器不全

Academic Significance and Societal Importance of the Research Achievements

感染症が原因で臓器障害に進展して敗血症となると死亡率が高くなり予後が不良となる。臓器障害を進展させる原因となっているヒストンH3と呼ばれる物質に着目して、この物質を抑える可能性を持つトロンボモジュリンを用いて今回の検証をおこなった。結果として、トロンボモジュリンはヒストンH3を抑制して腎障害を軽減させる関連が示唆された。敗血症の予後を改善させるためのあらたな創薬の可能性と患者の予後を改善さえることで社会経済的にも大きな影響を及ぼすものと考えられる。