HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo

Andrew Lilja, Clare E. Weeden, Kate McArthur, Thao Nguyen, Alastair Donald, Zi Xin Wong, Lovisa Dousha, Steve Bozinovski, Ross Vlahos, Christopher J. Burns, Marie Liesse Asselin-Labat, Gary P. Anderson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10-100mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dosedependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung.

Original languageEnglish (US)
Article numbere0114975
JournalPloS one
Volume10
Issue number1
DOIs
StatePublished - Jan 23 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Lilja, A., Weeden, C. E., McArthur, K., Nguyen, T., Donald, A., Wong, Z. X., Dousha, L., Bozinovski, S., Vlahos, R., Burns, C. J., Asselin-Labat, M. L., & Anderson, G. P. (2015). HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. PloS one, 10(1), [e0114975]. https://doi.org/10.1371/journal.pone.0114975