Development of Novel Therapies Targeting Airway Smooth Muscle Dysregulation and Airway Hyperresponsiveness in Severe Asthma

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20924
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Miki Haruka 筑波大学, 医学医療系, 助教 (30789524)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 難治性喘息 / 気道過敏性 / 気道リモデリング / TNFSF14(LIGHT) / LTβR

Outline of Final Research Achievements

TNFSF14 (LIGHT) is a TNF family cytokine which is highly produced in patients with severe asthma. Higher levels of soluble LIGHT in the sputum or BALF correlate with lower lung function and increased asthma severity. We aimed to clarify the role of LIGHT on airway smooth muscle (ASM) cells by using a mouse model of asthma and human primary ASM cells. LIGHT promoted ASM differentiation, proliferation, and increased contractility through the LTβR receptor on ASM via non-canonical NFκB signaling. In ASM-specific LTβR-deficient mice, AHR and remodeling in severe asthma were improved, suggesting that LIGHT-LTβR signaling could be a novel therapeutic target for severe asthma.

Free Research Field

アレルギー

Academic Significance and Societal Importance of the Research Achievements

気道過敏性の残存や気道リモデリングは気管支喘息における難治病態であり、根本的治療は確立されていない。本研究ではLIGHTが気道平滑筋上のLTβRシグナルを介して気道平滑筋を直接制御することにより気道過敏性の亢進および気道リモデリングの促進に寄与していることを明らかにし、LIGHT-LTβRが重症喘息における難治病態に対する新規治療標的となる可能性を示唆した。