title: HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo.
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.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lilja
authors.affiliation: Division of ACRF Stem Cells and Cancer, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Weeden
authors.affiliation: Division of Chemical Biology, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: McArthur
authors.affiliation: Division of Chemical Biology, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Thao
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Division of Chemical Biology, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Alastair
authors.initials: A
authors.lastname: Donald
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Zi Xin
authors.initials: ZX
authors.lastname: Wong
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Dousha
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Bozinovski
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.affiliation: Division of Chemical Biology, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: Division of ACRF Stem Cells and Cancer, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia.
authors.forename: Marie-Liesse
authors.initials: ML
authors.lastname: Asselin-Labat
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, 3010 VIC, Australia.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016227:Benzoquinones / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; C533237:STA 9090; D014230:Triazoles; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C001277:geldanamycin