Small molecule inhibition of IRE1 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 proteins response (UPR) that either restores homeostasis or...

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Published inbioRxiv
Main Authors 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
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 23.08.2018
Subjects
Alveoli
Apoptosis
Bleomycin
Endoplasmic reticulum
Epithelial cells
Fibrosis
Homeostasis
Kinases
Lung diseases
Lungs
Pulmonary fibrosis
Respiration
Signal transduction
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Summary: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 proteins response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1 is a UPR sensor that promotes apoptosis if ER stress remains high (i.e., a 'terminal' UPR). Using multiple small molecule inhibitors against IRE1 , 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 IRE1 and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1 kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the importance of IRE1 activation in bleomycin-induced mouse 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 the reversal of established fibrosis. These results demonstrate that IRE1 may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1 may eventually be developed into efficacious anti-fibrotic drugs.
DOI:10.1101/398552