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HSP90 inhibitor geldanamycin reverts IL-13– and IL-17–induced airway goblet cell metaplasia
Alejandro A. Pezzulo, … , Nicholas D. Gansemer, Joseph Zabner
Alejandro A. Pezzulo, … , Nicholas D. Gansemer, Joseph Zabner
Published January 14, 2019
Citation Information: J Clin Invest. 2019;129(2):744-758. https://doi.org/10.1172/JCI123524.
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Research Article Inflammation Pulmonology

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

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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.

Authors

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

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Figure 2

The response to IL-13 in vitro partially recapitulates the in vivo transcriptional profile of asthma in human airway epithelia.

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The response to IL-13 in vitro partially recapitulates the in vivo trans...
A microarray data set of primary human airway epithelia exposed to IL-13 (vs. vehicle) for 21 days (data set A) was generated. Characteristic direction (CD) analysis was performed to facilitate comparisons with other microarray data sets publicly available in the GEO database. A cutoff of the top-500 genes was used for the characteristic direction analysis. Two data sets were derived from bronchial (data set B) and nasal (data set C) epithelia exposed to IL-13 (vs. vehicle) in vitro, and three data sets (data sets D–F) were derived from bronchial biopsies from patients with asthma and their controls. Heatmaps show the top-25 upregulated and downregulated genes compared with controls. Genes are ranked as the sum of characteristic directions from all data sets. Blank squares represent genes that did not pass the 500-gene cutoff for the respective data set. The analysis is publicly available at: amp.pharm.mssm.edu/gen3va/report/497/Pezzulo_IL13.
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