HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo

PLoS One. 2015 Jan 23;10(1):e0114975. doi: 10.1371/journal.pone.0114975. eCollection 2015.

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 (10-100 mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Benzoquinones / pharmacology
  • Cytokines / genetics
  • Cytokines / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Inflammation / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Lactams, Macrocyclic / pharmacology
  • Lipopolysaccharides / toxicity
  • Lung / drug effects
  • Lung / pathology*
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Triazoles / pharmacology

Substances

  • Benzoquinones
  • Cytokines
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Lipopolysaccharides
  • STA 9090
  • Triazoles
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • geldanamycin

Grants and funding

This work is supported by scholarships, fellowships and grants from the Australian National Health and Medical Research Council (Development Grant 1038895); Victorian State Government Operational Infrastructure Support (OIS) Grant; Australian Cancer Research Foundation; Australian Research Council Queen Elizabeth II Fellowship (MLAL); and, Dyson Bequest funding (Dunn Fellowship to CJB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.