Development of novel antifibrotic therpy for idiopathic pulmonary fibrosis via suppression of the activity of M2c-macrophages

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17234
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Shibata Eisuke 兵庫医科大学, 医学部, 助教 (00774613)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 特発性肺線維症 / M2マクロファージ / 線維化 / Hippo pathway

Outline of Final Research Achievements

Idiopathic pulmonary fibrosis (IPF) is chronic progressive disease and is difficult to treat. In the present study, we investigated the role of alternatively activated M2 macrophages which supposed to be a regulator of both inflammation and fibrosis. At first, we speculated that activation of transcriptional co-factor YAP/TAZ caused fibrosis through the induction of the expression of profibrotic genes such as CTGF and TGF-beta. According to our hypothesis, we differentiated THP-1 cells into macrophages by PMA thereafter stimulated them with various cytokines, and analyzed the expression of CTGF. However, induction of CTGF expression in THP-1-derived macrophages was not inhibited by knockdown of YAP/TAZ. Moreover, only low level of gene expression of YAP/TAZ was observed in them. These results suggested that macrophages were activated through the secretary factors from alveolar epithelial type II cells. We currently examined the expression of YAP/TAZ inducible genes in A549 cells.

Free Research Field

間質性肺炎、胸部悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

IPFに対してはこれまで長きに渡りステロイドによる治療が行われてきたが、有害事象が必発な上、有用性を示唆する科学的根拠はなく、ステロイド治療に抵抗性である。その理由については分かっていないが、申請者はたとえ炎症は抑える事ができても、それに続く線維化を抑える事ができない事、すなわち、ステロイドによって誘導されるM2c-MΦが線維芽細胞を活性化させ、筋線維芽細胞の増殖を促進する事が理由の一つと考えている。Ⅱ型肺胞上皮細胞におけるYAP/TAZの不活化により、M2MΦを抑制し、「炎症」と「線維化」の両方を制御する事が可能となれば、IPF治療のbreakthroughとなると考えている。