The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS
| Project/Area Number |
19K17837
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
Furukawa Miki 福島県立医科大学, 医学部, 博士研究員 (80722537)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Discontinued (Fiscal Year 2022)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 急性呼吸窮迫症候群 (ARDS) / 急性肺傷害 (ALI) / Gas6 / Mer / 敗血症 / ARDS / 血管内細胞 / ADDS |
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| Outline of Research at the Start |
TAM受容体（Tyro3, Axl, Mer）は自己免疫疾患や悪性腫瘍の病態に関与する。リガンドはGas6及びプロテインSである。抗癌剤による骨髄抑制、造血幹細胞移植で発症する敗血症に続発するARDSは、高サイトカイン血症による肺胞・毛細血管関門に生じる炎症傷害により血管透過性亢進型の肺水腫を呈し呼吸不全に至る。ARDSの病態には、サイトカインによる内皮細胞障害や血小板血栓、凝固異常がARDSの病態に寄与する。我々は選択的TAM阻害剤がARDSマウスのBALの好中球及び単球を著明に減少させ、重症肺障害を改善させることを示した。本研究はARDSの新たな治療薬候補、バイオマーカーの発見を目的とする
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| Outline of Final Research Achievements |
The pathogenesis of sepsis-induced ALI/ARDS has not yet been fully elucidated. Gas6 has significant effects on hemostasis and inflammation through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl, and Mer. The plasma Gas6 and soluble Mer levels are higher in patients with severe sepsis and/or septic ALI/ARDS. To determine whether the Gas6-Mer axis is critical in the pathogenesis of ALI/ARDS, mouse models after 5 mg/ml LPS inhalation were used, and we further investigated the effects of intravenous administration of 2 mg/kg UNC2250, a selective Mer inhibitor, on LPS-induced ALI in the mouse models. UNC2250 markedly inhibited increased infiltration of neutrophils and monocytes overexpressing Gas6 and Mer proteins, severe lung damage, and increased levels of reactive oxygen species in LPS-induced ALI in the mouse models. Our study provides critical insights into Mer inhibition as a therapeutic target for inflammatory responses in ALI/ARDS.
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| Academic Significance and Societal Importance of the Research Achievements |
血液腫瘍の化学療法や造血幹細胞移植は、造血障害と免疫不全を伴い、重症感染症に対して極めて脆弱である、重症感染症に続発するALI/ARDSは生命予後を左右する。しかし、未だ治療法が確立されていない。これまで、Gas6とその受容体Merが、多発性骨髄腫の進行 (J Biol Chem. 2017;292:4280) や、造血幹細胞移植における急性GVHD及びTMA (Blood Adv. 2009;3:2128) に関与していることを報告した。本研究では、ALI/ARDSにおけるGas6-Mer経路に着目した解析を行い、ALI/ARDSの治療薬として、Mer阻害剤が有用であることを明らかにした。
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Report
(4 results)
Research Products
(5 results)
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[Journal Article] The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS2022
Author(s)
Fukatsu M, Ohkawara H, Wang X, Alkebsi L, Furukawa M, Mori H, Fukami M, Fukami SI, Sano T, Takahashi H, Harada-Shirado K, Kimura S, Sugimoto K, Ogawa K, Ikezoe T
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Journal Title
Sci Signal.
Volume: 15
Pages: 724-724
Related Report
Peer Reviewed
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[Journal Article] A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD2019
Author(s)
Miki Furukawa, Xintao Wang, Hiroshi Ohkawara, Masahiko Fukatsu, Lobna Alkebsi, Hiroshi Takahashi, Kayo Harada-Shirado, Akiko Shichishima-Nakamura, Satoshi Kimura, Kazuei Ogawa, Takayuki Ikezoe
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Journal Title
Blood Adv.
Volume: 3(14):
Pages: 2128-2143
Related Report
Peer Reviewed / Open Access
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