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HSP90 inhibitor geldanamycin reverts IL-13- and IL-17-induced airway goblet cell metaplasia

Authors :
Pezzulo, Alejandro A.
Tudas, Rosarie A.
Stewart, Carley G.
Buonfiglio, Luis G. Vargas
Lindsay, Brian D.
Taft, Peter J.
Gansemer, Nicholas D.
Zabner, Joseph
Source :
Journal of Clinical Investigation. February, 2019, Vol. 129 Issue 2, p744, 15 p.
Publication Year :
2019

Abstract

Goblet cell metaplasia, a disabling hallmark of chronic lung disease, lacks curative treatments at present. To identify novel therapeutic targets for goblet cell metaplasia, we studied the transcriptional response profile of IL-13-exposed primary human airway epithelia in vitro and asthmatic airway epithelia in vivo. A perturbation-response profile connectivity approach identified geldanamycin, an inhibitor of heat shock protein 90 (HSP90) as a candidate therapeutic target. Our experiments confirmed that geldanamycin and other HSP90 inhibitors prevented IL-13-induced goblet cell metaplasia in vitro and in vivo. Geldanamycin also reverted established goblet cell metaplasia. Geldanamycin did not induce goblet cell death, nor did it solely block mucin synthesis or IL-13 receptor-proximal signaling. Geldanamycin affected the transcriptome of airway cells when exposed to IL-13, but not when exposed to vehicle. We hypothesized that the mechanism of action probably involves TGF-[beta], ERBB, or EHF, which would predict that geldanamycin would also revert IL-17-induced goblet cell metaplasia, a prediction confirmed by our experiments. Our findings suggest that persistent airway goblet cell metaplasia requires HSP90 activity and that HSP90 inhibitors will revert goblet cell metaplasia, despite active upstream inflammatory signaling. Moreover, HSP90 inhibitors may be a therapeutic option for airway diseases with goblet cell metaplasia of unknown mechanism.<br />Introduction Human lungs constantly interact with the environment. In some individuals, various environmental exposures cause chronic mucus hypersecretion, leading to disability and reduced quality of life (1-3). Goblet cell metaplasia [...]

Details

Language :
English
ISSN :
00219738
Volume :
129
Issue :
2
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.574176420
Full Text :
https://doi.org/10.1172/JCI123524