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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 7

HSP90 inhibition prevents IL-13–induced airway goblet cell metaplasia in mice in vivo.

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HSP90 inhibition prevents IL-13–induced airway goblet cell metaplasia in...
Mice were exposed via intranasal delivery to vehicle, geldanamycin, IL-13 (2.5 μg in 50 μl PBS, 50 μg/ml), or IL-13 plus geldanamycin (25 μM) daily for 4 days. After exposure, lungs were fixed, sectioned and stained with dPAS. Goblet cell abundance was scored for individual airways. (A) Images of whole lung sections (red asterisks indicate individual airways). (B–E) Representative airway images from each treatment group. An average of 40 airways per mouse were scored. (F) Goblet cell abundance. Data represent the mean ± SEM (n = 6 mice per group). *P < 0.05, by ordinary repeated-measures ANOVA with Tukey’s adjustment. Scale bars: 500 μm (A) and 20 μm (B–E).
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