Effects of HSP90 inhibitors on airway goblet cell metaplasia

Goblet cell metaplasia and mucus hypersecretion are disabling hallmarks of chronic lung diseases for which no curative treatments are available. Therapies targeting specific upstream drivers of asthma have had variable results. We hypothesized that an a priori-knowledge independent approach would point to new therapies for airway goblet cell metaplasia. We analyzed the transcriptome of an organotypic model of human goblet cell metaplasia. We combined our data with previously published datasets from IL13-exposed in vitro and asthmatic in vivo human airway epithelial cells. The drug perturbation-response connectivity approach identified the heat shock protein 90 (HSP90) inhibitor geldanamycin as a candidate for reverting airway goblet cell metaplasia. We found that geldanamycin not only prevented but reverted IL13-induced goblet cell metaplasia. Geldanamycin did not induce goblet cell death, did not solely block mucin synthesis, and did not block IL13 receptor-proximal signaling. Moreover, the transcriptional effects of geldanamycin were absent in unstimulated cells and became evident only after stimulation with IL13. The predicted mechanism of action suggested that geldanamycin should also revert IL17-induced goblet cell metaplasia, a prediction confirmed by our data. Our findings suggest HSP90 activity may be required for persistence of goblet cell metaplasia driven by various mechanisms in chronic lung diseases. Overall design: For both batches, airway epithelia cultures from the lungs of eight different humans were studied, therefore, there are eight biological replicates. Comparisons should be made within batches. In batch 1 (XAM1), epithelia were exposed to vehicle (DMSO 0.5%), geldanamycin 25 uM, or the HDAC6 inhibitor ISOX 10 uM for 48 hours. In batch 2 (XAM3), the epithelia were exposed to vehicle (DMSO 0.5%), IL13 (20 ng/mL) or IL13 plus geldanamycin (10 uM) for 48 hours.

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Pezzulo AA, Tudas RA, Stewart CG, Buonfiglio LGV, Lindsay BD, Taft PJ, Gansemer ND, Zabner J