Inhibiting Skp2 E3 ligase suppresses bleomycin-induced pulmonary fibrosis

Masashi Mikamo, Kyoko Kitagawa, Satoshi Sakai, Chiharu Uchida, Tatsuya Ohhata, Koji Nishimoto, Hiroyuki Niida, Sayuri Suzuki, Keiichi I. Nakayama, Naoki Inui, Takafumi Suda, Masatoshi Kitagawa

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF.

Original languageEnglish
Article number474
JournalInternational journal of molecular sciences
Volume19
Issue number2
DOIs
Publication statusPublished - Feb 6 2018

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Inhibiting Skp2 E3 ligase suppresses bleomycin-induced pulmonary fibrosis'. Together they form a unique fingerprint.

  • Cite this

    Mikamo, M., Kitagawa, K., Sakai, S., Uchida, C., Ohhata, T., Nishimoto, K., Niida, H., Suzuki, S., Nakayama, K. I., Inui, N., Suda, T., & Kitagawa, M. (2018). Inhibiting Skp2 E3 ligase suppresses bleomycin-induced pulmonary fibrosis. International journal of molecular sciences, 19(2), [474]. https://doi.org/10.3390/ijms19020474