Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice

Naoki Hamada, Kazuyoshi Kuwano, Mizuho Yamada, Naoki Hagimoto, Kenichi Hiasa, Kensuke Egashira, Nobutaka Nakashima, Takashige Maeyama, Michihiro Yoshimi, Yoichi Nakanishi

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126 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenesis factor with proinflammatory roles. Fit-1 is one of the specific receptors for VEGF, and soluble flt-1 (sflt-1) binds to VEGF and competitively inhibits it from binding to the receptors. We examined the role of VEGF in the pathophysiology of bleomycin-induced pneumopathy in mice, using a new therapeutic strategy that comprises transfecticm of the sflt-1 gene into skeletal muscles as a biofactory for anti-VEGF therapy. The serum levels of sflt-1 were significantly increased at 3-14 days after the gene transfer. Transfection of the sflt-1 gene at 3 days before or 7 days after the intratracheal instillation of bleomycin decreased the number of inflammatory cells, the protein concentration in the bronchoalveolar lavage fluid and with von Willebrand factor expression at 14 days. Transfection of the sflt-1 gene also attenuated pulmonary flbrosis and apoptosis at 14 days. Since the inflammatory cell infiltration begins at 3 days and is followed by interstitial flbrosis, it is likely that VEGF has important roles as a proinflammatory, a permeability-inducing, and an angiogenesis factor not only in the early inflammatory phase but also in the late fibrotic phase. Furthermore, this method may be beneficial for treating lung injury and flbrosis from the viewpoint of clinical application, since it does not require the use of a viral vector or neutralizing Ab.

Original languageEnglish
Pages (from-to)1224-1231
Number of pages8
JournalJournal of Immunology
Volume175
Issue number2
DOIs
Publication statusPublished - Jul 15 2005

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Hamada, N., Kuwano, K., Yamada, M., Hagimoto, N., Hiasa, K., Egashira, K., Nakashima, N., Maeyama, T., Yoshimi, M., & Nakanishi, Y. (2005). Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. Journal of Immunology, 175(2), 1224-1231. https://doi.org/10.4049/jimmunol.175.2.1224