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

• Published in: PloS one 2019-01, Vol.14 (1), p.e0209824
• 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: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - pathology; Alveoli; Animals; Apoptosis; Apoptosis - drug effects; Attenuators; Biochemistry; Biology; Biology and Life Sciences; Bleomycin; Cell Line; Critical care; Diabetes; Disease; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - antagonists & inhibitors; Epithelial cells; Exposure; Fibrosis; Fibrosis - drug therapy; Fibrosis - metabolism; Fibrosis - pathology; Homeostasis; Inhibitors; Kinases; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Medicine; Medicine and Health Sciences; Mice; Mutation; Pathogenesis; Protein folding; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Proteins; Pulmonary fibrosis; Research and Analysis Methods; Respiration; Respiratory failure; Signal transduction; Signaling; Sleep; Stress; Surfactants; Transcription factors; Unfolded Protein Response - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0209824

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.