HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo.
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 mult...
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doaj-cb1257f818d240afaad8c2a8edb75f392020-11-25T01:33:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01101e011497510.1371/journal.pone.0114975HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo.Andrew LiljaClare E WeedenKate McArthurThao NguyenAlastair DonaldZi Xin WongLovisa DoushaSteve BozinovskiRoss VlahosChristopher J BurnsMarie-Liesse Asselin-LabatGary P AndersonInflammation 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.http://europepmc.org/articles/PMC4304786?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. PLoS ONE |
author_facet |
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 |
author_sort |
Andrew Lilja |
title |
HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
title_short |
HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
title_full |
HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
title_fullStr |
HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
title_full_unstemmed |
HSP90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
title_sort |
hsp90 inhibition suppresses lipopolysaccharide-induced lung inflammation in vivo. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4304786?pdf=render |
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