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

Alejandro A Pezzulo; Rosarie A Tudas; Carley G Stewart; Luis G. Vargas Buonfiglio; Brian D Lindsay; Peter J Taft; Nicholas D Gansemer; Joseph Zabner

doi:10.1172/JCI123524

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

Journal article

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

Alejandro A Pezzulo, Rosarie A Tudas, Carley G Stewart, Luis G. Vargas Buonfiglio, Brian D Lindsay, Peter J Taft, Nicholas D Gansemer and Joseph Zabner

The Journal of clinical investigation, Vol.129(2), pp.744-758

02/01/2019

DOI: 10.1172/JCI123524

PMCID: PMC6355221

PMID: 30640172

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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-β, 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.

Pulmonology

Allergy

Inflammation

Asthma

COPD

Details

Title: Subtitle: HSP90 inhibitor geldanamycin reverts IL-13– and IL-17–induced airway goblet cell metaplasia
Creators: Alejandro A Pezzulo - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Rosarie A Tudas - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Carley G Stewart - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Luis G. Vargas Buonfiglio - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Brian D Lindsay - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Peter J Taft - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Nicholas D Gansemer - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Joseph Zabner - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.129(2), pp.744-758
DOI: 10.1172/JCI123524
PMID: 30640172
PMCID: PMC6355221
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Grant note: Francis Fellowship Program / Parker B. Francis Foundation
Language: English
Date published: 02/01/2019
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Internal Medicine
Record Identifier: 9984094752702771

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