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.
Highlights
We further show that ER stress and stereotypic terminal unfolded protein response (UPR) signature changes occur early in mouse models of bleomycin-induced pulmonary fibrosis, and that administration of a kinase-inhibiting RNase attenuators (KIRAs) compound at the time of bleomycin exposure prevents the full fibrosis phenotype
ER stress-induced apoptosis in alveolar epithelial cells depends on IRE1α activity
We have shown that ER stress induces apoptosis in a mouse alveolar epithelial cell line and mouse primary type II alveolar epithelial cells, and that inhibiting the IRE1α RNase mitigates apoptosis in vitro
Summary
The unfolded protein response (UPR) is a conserved intracellular signaling pathway that is activated when eukaryotic cells experience protein folding stress in the endoplasmic reticulum. Hyperactivated IRE1α cleaves and degrades the precursor of the microRNA, miR-17, which in turn relieves gene repression of thioredoxin-interacting protein (TXNIP) This pathway culminates in apoptosis and is called the “terminal UPR” [10]; terminal UPR signaling underlies several diseases of premature cell loss [11]. Administration of the nonspecific “chemical chaperones” 4-PBA or TUDCA mitigated fibrosis after bleomycin injury [22] Together, these findings suggest that dampening UPR signaling, perhaps through inhibiting IRE1α, might provide therapeutic benefit in IPF. These findings suggest that dampening UPR signaling, perhaps through inhibiting IRE1α, might provide therapeutic benefit in IPF To these ends, our groups have developed small-molecule compounds that inhibit the IRE1α kinase and thereby allosterically regulate its RNase activity [23,24,25]. These studies suggest the possible benefit of the KIRA class of compounds in human IPF
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