HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis.

Autor: Delbrel, Eva, Soumare, Abdoulaye, Naguez, Adnan, Label, Rabab, Bernard, Olivier, Bruhat, Alain, Fafournoux, Pierre, Tremblais, Geoffrey, Marchant, Dominique, Gille, Thomas, Bernaudin, Jean-François, Callard, Patrice, Kambouchner, Marianne, Martinod, Emmanuel, Valeyre, Dominique, Uzunhan, Yurdagül, Planès, Carole, Boncoeur, Emilie
Zdroj: Scientific Reports; 12/18/2018, Vol. 8 Issue 1, p1-1, 1p
Abstrakt: Endoplasmic Reticulum (ER) stress of alveolar epithelial cells (AECs) is recognized as a key event of cell dysfunction in pulmonary fibrosis (PF). However, the mechanisms leading to AECs ER stress and ensuing unfolded protein response (UPR) pathways in idiopathic PF (IPF) remain unclear. We hypothesized that alveolar hypoxic microenvironment would generate ER stress and AECs apoptosis through the hypoxia-inducible factor-1α (HIF-1α). Combining ex vivo, in vivo and in vitro experiments, we investigated the effects of hypoxia on the UPR pathways and ER stress-mediated apoptosis, and consecutively the mechanisms linking hypoxia, HIF-1α, UPR and apoptosis. HIF-1α and the pro-apoptotic ER stress marker C/EBP homologous protein (CHOP) were co-expressed in hyperplastic AECs from bleomycin-treated mice and IPF lungs, not in controls. Hypoxic exposure of rat lungs or primary rat AECs induced HIF-1α, CHOP and apoptosis markers expression. In primary AECs, hypoxia activated UPR pathways. Pharmacological ER stress inhibitors and pharmacological inhibition or silencing of HIF-1α both prevented hypoxia-induced upregulation of CHOP and apoptosis. Interestingly, overexpression of HIF-1α in normoxic AECs increased UPR pathways transcription factors activities, and CHOP expression. These results indicate that hypoxia and HIF-1α can trigger ER stress and CHOP-mediated apoptosis in AECs, suggesting their potential contribution to the development of IPF. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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