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Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung

Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or p...

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Autores principales: Thamsen, Maike, Ghosh, Rajarshi, Auyeung, Vincent C., Brumwell, Alexis, Chapman, Harold A., Backes, Bradley J., Perara, Gayani, Maly, Dustin J., Sheppard, Dean, Papa, Feroz R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326459/
https://www.ncbi.nlm.nih.gov/pubmed/30625178
http://dx.doi.org/10.1371/journal.pone.0209824
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author Thamsen, Maike
Ghosh, Rajarshi
Auyeung, Vincent C.
Brumwell, Alexis
Chapman, Harold A.
Backes, Bradley J.
Perara, Gayani
Maly, Dustin J.
Sheppard, Dean
Papa, Feroz R.
author_facet Thamsen, Maike
Ghosh, Rajarshi
Auyeung, Vincent C.
Brumwell, Alexis
Chapman, Harold A.
Backes, Bradley J.
Perara, Gayani
Maly, Dustin J.
Sheppard, Dean
Papa, Feroz R.
author_sort Thamsen, Maike
collection PubMed
description Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1α is a UPR sensor/effector that promotes apoptosis if ER stress remains high and irremediable (i.e., a “terminal” UPR). Using multiple small molecule inhibitors against IRE1α, we show that ER stress-induced apoptosis of murine alveolar epithelial cells can be mitigated in vitro. In vivo, we show that bleomycin exposure to murine lungs causes early ER stress to activate IRE1α and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1α kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the contribution of IRE1α activation to bleomycin-induced pulmonary fibrosis. One such KIRA—KIRA7—provided systemically to mice at the time of bleomycin exposure decreases terminal UPR signaling and prevents lung fibrosis. Administration of KIRA7 14 days after bleomycin exposure even promoted the reversal of established fibrosis. Finally, we show that KIRA8, a nanomolar-potent, monoselective KIRA compound derived from a completely different scaffold than KIRA7, likewise promoted reversal of established fibrosis. These results demonstrate that IRE1α may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1α may eventually be developed into efficacious anti-fibrotic drugs.
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spelling pubmed-63264592019-01-18 Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung Thamsen, Maike Ghosh, Rajarshi Auyeung, Vincent C. Brumwell, Alexis Chapman, Harold A. Backes, Bradley J. Perara, Gayani Maly, Dustin J. Sheppard, Dean Papa, Feroz R. PLoS One Research Article Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1α is a UPR sensor/effector that promotes apoptosis if ER stress remains high and irremediable (i.e., a “terminal” UPR). Using multiple small molecule inhibitors against IRE1α, we show that ER stress-induced apoptosis of murine alveolar epithelial cells can be mitigated in vitro. In vivo, we show that bleomycin exposure to murine lungs causes early ER stress to activate IRE1α and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1α kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the contribution of IRE1α activation to bleomycin-induced pulmonary fibrosis. One such KIRA—KIRA7—provided systemically to mice at the time of bleomycin exposure decreases terminal UPR signaling and prevents lung fibrosis. Administration of KIRA7 14 days after bleomycin exposure even promoted the reversal of established fibrosis. Finally, we show that KIRA8, a nanomolar-potent, monoselective KIRA compound derived from a completely different scaffold than KIRA7, likewise promoted reversal of established fibrosis. These results demonstrate that IRE1α may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1α may eventually be developed into efficacious anti-fibrotic drugs. Public Library of Science 2019-01-09 /pmc/articles/PMC6326459/ /pubmed/30625178 http://dx.doi.org/10.1371/journal.pone.0209824 Text en © 2019 Thamsen et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Thamsen, Maike
Ghosh, Rajarshi
Auyeung, Vincent C.
Brumwell, Alexis
Chapman, Harold A.
Backes, Bradley J.
Perara, Gayani
Maly, Dustin J.
Sheppard, Dean
Papa, Feroz R.
Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title_full Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title_fullStr Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title_full_unstemmed Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title_short Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung
title_sort small molecule inhibition of ire1α kinase/rnase has anti-fibrotic effects in the lung
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326459/
https://www.ncbi.nlm.nih.gov/pubmed/30625178
http://dx.doi.org/10.1371/journal.pone.0209824
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