Exploring the Molecular Pathogenesis of Pulmonary Alveolar Microlithiasis and Developing Novel Therapeutic Approaches Using Integrated Omics Analysis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08521
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Sapporo Medical University
• Principal Investigator: SAITO ATSUSHI 札幌医科大学, 医学部, 講師 (00768939)
• Co-Investigator(Kenkyū-buntansha): 藤谷 直樹 札幌医科大学, 医学部, 助教 (10374191) ; 高宮 里奈 東京大学, 大学院医学系研究科(医学部), 特任助教 (70365419)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肺胞微石症 / リン酸トランスポーター / 希少肺疾患

Outline of Final Research Achievements

PAM is a rare autosomal recessive lung disorder caused by genetic abnormalities in the Npt2b, leading to the formation of calcium phosphate stones within the alveolar spaces. Through pathogenesis analysis using a PAM mouse model, it was observed that intrapulmonary administration of clodronate liposomes increased microlith accumulation, suggesting the involvement of alveolar macrophages in microlith removal from the alveoli. Furthermore, lipidomics analysis revealed significant elevation of arachidonic acid and other eicosanoids, as well as COX-2. It was found that downstream signaling molecules such as PGE2 and LXA4, which are anti-inflammatory mediators, were significantly increased, indicating their role in suppressing inflammation in the lungs associated with microlith formation. Additionally, COX-2 expression was significantly decreased with the previously reported therapy involving phosphate-binding agents, reaffirming the effectiveness of this treatment approach.

Free Research Field

呼吸器病学

Academic Significance and Societal Importance of the Research Achievements

肺胞微石症のような超希少疾患は対象患者が少ないこともあり、研究者も少なく病態解明がなかなか進まないことが多い。本研究ではマウスモデルを用いることで新たに病態解明を進めることができた。本研究の結果は今後臨床応用されることで本疾患に苦しむ患者に対する希望となると考える。