2023 Fiscal Year Final Research Report
Association between oxidative stress and Type2 inflammation in asthma
| Project/Area Number |
21K16117
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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 53030:Respiratory medicine-related
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| Research Institution | Kindai University (2023)
Kyoto University (2021-2022) |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | asthma / redox balance / glutathione / ferroptosis / SLC7A11 / 15 lipoxygenase-1 / Type-2 inflammation |
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| Outline of Final Research Achievements |
GSSG was higher and GSH:GSSG lower in asthmatic compared to HC BAL fluid. In contrast, fresh asthmatic HAEC intracellular GSH levels were lower but correlated with BAL fluid GSH. In vitro, the T2 cytokine IL-13 induced. 15LO1 activity increased hydroperoxy-phospholipids, in association with lowered intracellular GSH and higher extracellular GSSG levels. Lowering GSH levels further by inhibiting SLC7A11 (erastin) enhanced T2 inflammatory protein expression and cell death. Ex vivo, GSH and GSSG-associated imbalances in redox biology corresponded with altered 15LO1 and SLC7A11 expression, increased ferroptotic phospholipids, as well as Type-2 biomarkers and worsened clinical outcomes. Thus, 15LO1 pathway activity-induced perturbations in GSH:GSSG promote T2 inflammation and poor asthma control. 15LO1 is a novel therapeutic target for asthma.
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| Free Research Field |
pulmonary medicine
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| Academic Significance and Societal Importance of the Research Achievements |
生物学的製剤を含めた喘息治療の進展にもかかわらず、難治性喘息がいまだ存在する。今までとは異なったアプローチから喘息治療を検討する必要がある。
喘息含めた疾患の病態生理において、酸化ストレスが関わっていることが示されており、近年、新しい細胞死であるフェロトーシスが喘息に関わっていることが明らかになった。
今回、フェロトーシスに関連あるグルタチオンを喘息患者および喘息患者の起動細胞を用いて検討した。2型炎症、15LO1、グルタチオン、フェロトーシスの関連を明らかにし、特に15LO1が新たな治療ターゲットとなる可能性を示した。
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