Mechanistic association of RAGE/HMGB1 axis with drug induced lung injury in lung cancer

• Project/Area Number: 18K15951
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hiroshima University
• Principal Investigator: Yamaguchi Kakuhiro 広島大学, 病院(医), 助教 (90812991)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 薬剤性肺障害 / 肺癌 / 細胞障害性抗がん剤 / HMGB1 / sRAGE / 間質性肺炎 / RAGE / 肺がん / 薬剤性肺傷害

Outline of Final Research Achievements

This study was conducted to investigate the first predictive blood biomarker for cytotoxic chemotherapy induced lung injury as a life-threatening complication in patients with lung cancer concomitant with interstitial lung disease (ILD). We found an independent association between serum HMGB1 levels and the onset of chemotherapy-induced lung injury in these patients . Additionally, exploratory analysis revealed that higher levels of serum sRAGE, a decoy receptor for RAGE ligands including HMGB1, was associated with decreased incidence of cytotoxic chemotherapy-induced lung injury in patients with higher HMGB1 levels. These results indicate that HMGB1 is a promising biomarker and may have a role in the pathogenesis of cytotoxic
chemotherapy-induced lung injury in patients with lung cancer and ILD.

Academic Significance and Societal Importance of the Research Achievements

肺癌は癌の中で死亡者数が最多であり、加えて喫煙と強く関連する癌腫であるため、もともと肺に間質性肺炎などの器質的異常を伴う頻度が高い。間質性肺炎を合併する患者は全体の10-15%という報告があるが、そのような患者では各種薬剤による肺障害のリスクが高く、標準治療を行えないばかりか肺障害のリスクの高さから緩和的治療に終止する場合もある。本研究では、血液マーカーを用いて肺障害の予測精度を高め、またその分子生物学的な発症機序の一端を解明することで、間質性肺炎を合併した肺癌患者に対する治療の最適化および予防的な介入の確立に向けた研究の基盤となるデータをえることができたと考えている。

Research Products

• [Journal Article] Serum high-mobility group box 1 as a predictive marker for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and interstitial lung disease. (2020)
  • Author(s): Nakao S, Yamaguchi K, Iwamoto H, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Ohshimo S, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Respir Med. Volume: 172 Pages: 106131-106131
  • DOI: 10.1016/j.rmed.2020.106131
  • Peer Reviewed
• [Presentation] Pivotal role of the HMGB1/sRAGE axis in drug-induced lung injury in advanced lung cancer with pre-existing interstitial lung disease (2020)
  • Author(s): Nakao S, Yamaguchi K, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Iwamoto H, Ohshimo S, Fujitaka K, Hamada H, Hattori N.
  • Organizer: 30th International Congress of the European Respiratory Society
• [Presentation] 間質性肺炎合併肺癌における化学療法による間質性肺炎急性増悪発症予測因子としての血中HMGB1・sRAGEの有用性 (2020)
  • Author(s): 中尾聡志, 山口覚博, 坂本信二郎, 堀益靖, 益田武, 宮本真太郎, 中島拓, 岩本博志, 藤高一慶, 濱田泰伸, 服部登
  • Organizer: 第61回日本肺癌学会学術総会