Abstract
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.
Highlights
Idiopathic pulmonary fibrosis (IPF), the most common and severe form of interstitial lung diseases, is pathologically characterized by a pattern of usual interstitial pneumonia (UIP) associating fibrotic remodelling leading to honeycombing and abnormal characteristics of the alveolar epithelial cells (AECs)[1]
Considering the fact that hypoxia may promote endoplasmic reticulum (ER) stress in various organs[17,18], and that the expression of the hypoxia-inducible factor 1α (HIF-1α) has been previously reported in AECs from IPF lungs[19], we hypothesized that localized alveolar hypoxia and HIF-1α could be relevant stressors inducing prolonged ER stress and subsequent apoptosis of AECs in sporadic IPF
Our results show that HIF-1α and C/EBP homologous protein (CHOP) proteins were both detected in hyperplastic AECs observed in IPF patients’ lung biopsies and in bleomycin-induced pulmonary fibrosis in mice as well as in AECs from rat exposed to acute hypoxia
Summary
Idiopathic pulmonary fibrosis (IPF), the most common and severe form of interstitial lung diseases, is pathologically characterized by a pattern of usual interstitial pneumonia (UIP) associating fibrotic remodelling leading to honeycombing and abnormal characteristics of the alveolar epithelial cells (AECs)[1]. The objectives of the present study were: (1) to determine whether HIF-1α and CHOP proteins were co-expressed by AECs in lung tissue from IPF patients; (2) to evaluate whether micro-environmental hypoxia could activate the UPR pathways in rat AECs; (3) to decipher the molecular mechanisms linking hypoxia, HIF-1α, ER stress and apoptosis in these cells. HIF-1α involvement in the regulation of the transcriptional capacity of ATF4 and ATF6α/ XBP1s on their specific responsive elements, and CHOP expression was shown. Taken together, these results suggest that localized hypoxia of the alveolar milieu and expression of HIF-1α could promote UPR pathways, CHOP expression and apoptosis in AECs, contributing to alveolar cell dysfunction and promoting lung fibrosis
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