Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of SFTPC
Motoyasu Hosokawa,
Ryuta Mikawa,
Atsuko Hagiwara,
Yukiko Okuno,
Tomonari Awaya,
Yuki Yamamoto,
Senye Takahashi,
Haruka Yamaki,
Mitsujiro Osawa,
Yasuhiro Setoguchi,
Megumu K. Saito,
Shinji Abe,
Toyohiro Hirai,
Shimpei Gotoh,
Masatoshi Hagiwara
Affiliations
Motoyasu Hosokawa
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Developmental Biology and Functional Genomics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Ryuta Mikawa
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
Atsuko Hagiwara
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Yukiko Okuno
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Tomonari Awaya
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Yuki Yamamoto
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Senye Takahashi
Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
Haruka Yamaki
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
Mitsujiro Osawa
Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
Yasuhiro Setoguchi
Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan
Megumu K. Saito
Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
Shinji Abe
Department of Respiratory Medicine Tokyo, Medical University Hospital, Shinjuku-ku, Tokyo 160-0023, Japan
Toyohiro Hirai
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Shimpei Gotoh
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Corresponding author
Masatoshi Hagiwara
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding author
Summary: Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of SFTPC cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveolar epithelial type 2 (AT2) cells differentiated from patient-derived induced pluripotent stem cells (iPSCs), we identified Cryptotanshinone (CPT) as a potential therapeutic agent for ILD. CPT decreased cell death induced by mutant SFTPC overexpression in A549 and HEK293 cells and ameliorated the bleomycin-induced contraction of the matrix in fibroblast-dependent alveolar organoids derived from iPSCs with SFTPC mutation. CPT and this screening strategy can apply to abnormal protein-folding-associated ILD and other protein-misfolding diseases.
