AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis

Jennifer Cross, Grant R. Stenton, Curtis Harwig, Csaba Szabo, Tiziana Genovese, Rosanna Di Paola, Emanuale Esposito, Salvatore Cuzzocrea, Lloyd F. Mackenzie

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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-β 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.

Original languageEnglish (US)
Pages (from-to)3045-3057
Number of pages13
JournalBritish Journal of Pharmacology
Volume174
Issue number18
DOIs
StatePublished - 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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    Cross, J., Stenton, G. R., Harwig, C., Szabo, C., Genovese, T., Di Paola, R., Esposito, E., Cuzzocrea, S., & Mackenzie, L. F. (2017). AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis. British Journal of Pharmacology, 174(18), 3045-3057. https://doi.org/10.1111/bph.13934