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CG223, a novel BET inhibitor, exerts TGF-ß1-mediated antifibrotic effects in a murine model of bleomycin-induced pulmonary fibrosis.
Kaneshita, Shunya; Kida, Takashi; Yoshioka, Makoto; Nishioka, Keisuke; Raje, Mithun; Sakashita, Aki; Hirano, Aiko; Sagawa, Tomoya; Kasahara, Akiko; Inoue, Takuya; Fujioka, Kazuki; Nagahara, Hidetake; Wada, Makoto; Kohno, Masataka; Strovel, Jeffrey W; Fletcher, Steven; Ashihara, Eishi; Kawahito, Yutaka.
Afiliación
  • Kaneshita S; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: shunya-k@koto.kpu-m.ac.jp.
  • Kida T; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: t-kida@koto.kpu-m.ac.jp.
  • Yoshioka M; ConverGene LLC. 3093 Beverly Lane, Unit C, Cambridge, MD, 21613, United States. Electronic address: myoshioka@convergenepharma.com.
  • Nishioka K; Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: din85051@koto.kpu-m.ac.jp.
  • Raje M; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD, 21201, United States. Electronic address: mithun.raje@rosalindfranklin.edu.
  • Sakashita A; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: aki0808@koto.kpu-m.ac.jp.
  • Hirano A; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: tomiaiko@koto.kpu-m.ac.jp.
  • Sagawa T; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: t-sagawa@koto.kpu-m.ac.jp.
  • Kasahara A; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: matsusue@koto.kpu-m.ac.jp.
  • Inoue T; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: tinoue@koto.kpu-m.ac.jp.
  • Fujioka K; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: k-fjok@koto.kpu-m.ac.jp.
  • Nagahara H; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: naaga@koto.kpu-m.ac.jp.
  • Wada M; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: makoto-w@koto.kpu-m.ac.jp.
  • Kohno M; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: mkohno@koto.kpu-m.ac.jp.
  • Strovel JW; ConverGene LLC. 3093 Beverly Lane, Unit C, Cambridge, MD, 21613, United States. Electronic address: jstrovel@convergenepharma.com.
  • Fletcher S; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD, 21201, United States. Electronic address: steven.fletcher@rx.umaryland.edu.
  • Ashihara E; Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5, Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan. Electronic address: ash@mb.kyoto-phu.ac.jp.
  • Kawahito Y; Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. Electronic address: kawahity@koto.kpu-m.ac.jp.
Pulm Pharmacol Ther ; 70: 102057, 2021 10.
Article en En | MEDLINE | ID: mdl-34425215
Pulmonary fibrosis is a progressive disease with poor prognosis and limited therapeutic options. In this study, we evaluated the potential therapeutic effects of CG223, a novel inhibitor of bromodomain and extra-terminal motif (BET) proteins, on pulmonary fibrosis by focusing on the transforming growth factor-ß1 (TGF-ß1) pathway. In a murine model of bleomycin-induced pulmonary fibrosis, CG223 attenuated fibrosis while reducing the infiltration of inflammatory cells into the lungs. Fibroblasts expressing BRD4, a member of the BET protein family, were enriched in the tissue regions corresponding to bleomycin-induced fibrotic lesions. Additionally, pulmonary fibroblasts isolated from bleomycin-instilled mice showed a significantly increased association of BRD4 with the promoters of two pro-fibrotic genes linked to the entry into the TGF-ß1 autocrine/paracrine loop, thrombospondin 1 (Thbs1) and integrin ß3 (Itgb3), as well as with the promoter of a myofibroblast marker gene, actin alpha 2 (Acta2). Subsequent in vitro studies with murine primary lung fibroblasts showed that the mRNA induction of Thbs1, Itgb3, and Acta2 by TGF-ß1 can be inhibited by CG223 in a dose-dependent manner. Taken together, CG223-induced BRD4 inhibition suppressed lung fibrogenesis by affecting multiple genes, including those involved in the triggering of the TGF-ß1 autocrine/paracrine loop.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Bleomicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Pulm Pharmacol Ther Asunto de la revista: FARMACOLOGIA Año: 2021 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Bleomicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Pulm Pharmacol Ther Asunto de la revista: FARMACOLOGIA Año: 2021 Tipo del documento: Article Pais de publicación: Reino Unido