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ER Stress is Involved in Epithelial-To-Mesenchymal Transition of Alveolar Epithelial Cells Exposed to a Hypoxic Microenvironment.

AbstractBACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease of unknown origin. Alveolar epithelial cells (AECs) play an important role in the fibrotic process as they undergo sustained endoplasmic reticulum (ER) stress, and may acquire a mesenchymal phenotype through epithelial-to-mesenchymal transition (EMT), two phenomena that could be induced by localized alveolar hypoxia. Here we investigated the potential links between hypoxia, ER stress and EMT in AECs.
METHODS:
ER stress and EMT markers were assessed by immunohistochemistry, western blot and qPCR analysis, both in vivo in rat lungs exposed to normoxia or hypoxia (equivalent to 8% O₂) for 48 h, and in vitro in primary rat AECs exposed to normoxia or hypoxia (1.5% O₂) for 2⁻6 days.
RESULTS:
Hypoxia induced expression of mesenchymal markers, pro-EMT transcription factors, and the activation of ER stress markers both in vivo in rat lungs, and in vitro in AECs. In vitro, pharmacological inhibition of ER stress by 4-PBA limited hypoxia-induced EMT. Calcium chelation or hypoxia-inducible factor (HIF) inhibition also prevented EMT induction under hypoxic condition.
CONCLUSIONS:
Hypoxia and intracellular calcium are both involved in EMT induction of AECs, mainly through the activation of ER stress and HIF signaling pathways.
AuthorsEva Delbrel, Yurdagül Uzunhan, Abdoulaye Soumare, Thomas Gille, Dominique Marchant, Carole Planès, Emilie Boncoeur
JournalInternational journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 6 (Mar 14 2019) ISSN: 1422-0067 [Electronic] Switzerland
PMID30875855 (Publication Type: Journal Article)
Chemical References
  • 4-phenylbutylamine
  • Butylamines
  • Calcium Chelating Agents
  • Transcription Factors
  • Calcium
Topics
  • Alveolar Epithelial Cells (cytology, drug effects, metabolism)
  • Animals
  • Butylamines (pharmacology)
  • Calcium (metabolism)
  • Calcium Chelating Agents (pharmacology)
  • Cell Hypoxia (drug effects)
  • Cells, Cultured
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress (drug effects)
  • Epithelial-Mesenchymal Transition (drug effects)
  • Gene Expression Regulation (drug effects)
  • Humans
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors (metabolism)

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