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AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis.
Cross, Jennifer; Stenton, Grant R; Harwig, Curtis; Szabo, Csaba; Genovese, Tiziana; Di Paola, Rosanna; Esposito, Emanuale; Cuzzocrea, Salvatore; Mackenzie, Lloyd F.
Afiliación
  • Cross J; Aquinox Pharmaceuticals (Canada) Inc., Vancouver, BC, Canada.
  • Stenton GR; Aquinox Pharmaceuticals (Canada) Inc., Vancouver, BC, Canada.
  • Harwig C; Aquinox Pharmaceuticals (Canada) Inc., Vancouver, BC, Canada.
  • Szabo C; Aquinox Pharmaceuticals (Canada) Inc., Vancouver, BC, Canada.
  • Genovese T; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
  • Di Paola R; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
  • Esposito E; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy.
  • Cuzzocrea S; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
  • Mackenzie LF; Aquinox Pharmaceuticals (Canada) Inc., Vancouver, BC, Canada.
Br J Pharmacol ; 174(18): 3045-3057, 2017 Sep.
Article en En | MEDLINE | ID: mdl-28658529
BACKGROUND AND PURPOSE: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. EXPERIMENTAL APPROACH: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or dexamethasone (1 mg·kg-1 ·d-1 , i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or pirfenidone (90 mg·kg-1 ·d-1 , p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. KEY RESULTS: Given prophylactically, AQX-1125 (10 and 30 mg·kg-1 ) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-ß immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg-1 ) with corresponding improvements in disease severity. CONCLUSIONS AND IMPLICATIONS: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Bleomicina / Ciclohexanoles / Bibliotecas de Moléculas Pequeñas / Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas / Indanos Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Bleomicina / Ciclohexanoles / Bibliotecas de Moléculas Pequeñas / Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas / Indanos Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2017 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido