The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17837
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Furukawa Miki 福島県立医科大学, 医学部, 博士研究員 (80722537)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 急性呼吸窮迫症候群 (ARDS) / 急性肺傷害 (ALI) / Gas6 / Mer / 敗血症

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.

Free Research Field

敗血症誘発性の急性肺傷害（ALI）／急性呼吸窮迫症候群（ARDS）

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。