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PLoS One. 2019 Jan 9;14(1):e0209824. doi: 10.1371/journal.pone.0209824. eCollection 2019.

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

Thamsen M1,2,3,4, Ghosh R1,2,3,4, Auyeung VC1,4,5, Brumwell A1,5,6, Chapman HA1,5,6, Backes BJ1,2,4, Perara G7, Maly DJ7, Sheppard D1,4,5, Papa FR1,2,3,4,8.

Author information

1
Department of Medicine, University of California, San Francisco, California, United States of America.
2
Diabetes Center, University of California, San Francisco, California, United States of America.
3
Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, United States of America.
4
Lung Biology Center, University of California, San Francisco, California, United States of America.
5
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, California, United States of America.
6
Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.
7
Department of Chemistry and Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
8
Department of Pathology, University of California, San Francisco, California, United States of America.

Abstract

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.

PMID:
30625178
DOI:
10.1371/journal.pone.0209824
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Conflict of interest statement

The authors have declared that no competing interests exist.

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