PKR-dependent CHOP induction limits hyperoxia-induced lung injury

Area of Science:

• Pulmonary Medicine
• Cellular Biology
• Biochemistry

Background:

• Supplemental oxygen therapy is crucial for respiratory failure but can induce lung injury.
• Hyperoxia causes oxidative stress, inflammation, edema, and increased permeability in the lungs.
• The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in hyperoxia-induced lung injury is not fully understood.

Purpose of the Study:

• To investigate if oxidative stress from hyperoxia induces ER stress, UPR activation, and CCAAT enhancer-binding protein homologous protein (CHOP) expression.
• To determine the mechanism by which hyperoxia affects CHOP expression, specifically the role of PKR (double-stranded RNA-activated protein kinase).
• To elucidate the in vivo function of CHOP in hyperoxia-induced lung injury.

Main Methods:

• Exposing mouse lung epithelial cells (MLE-12) to 95% oxygen and assessing UPR and CHOP markers.
• Evaluating the role of PKR in hyperoxia-induced CHOP expression using RNA interference.
• Investigating hyperoxia effects on PKR and CHOP in mouse lungs and assessing lung injury in CHOP-null mice.

Main Results:

• Hyperoxia increased CHOP expression in MLE-12 cells without inducing other UPR markers.
• Hyperoxia induced PKR phosphorylation, and PKR knockdown attenuated CHOP expression.
• In vivo, hyperoxia increased PKR and CHOP phosphorylation in mouse lungs independently of ER stress.
• CHOP-null mice exhibited exacerbated lung edema and permeability, indicating a protective role for CHOP.

Conclusions:

• Hyperoxia upregulates CHOP through an ER stress-independent, PKR-dependent pathway.
• Contrary to initial hypotheses, CHOP plays a protective role in mitigating hyperoxia-induced lung injury.
• These findings reveal a novel mechanism and protective function of CHOP in the context of hyperoxia.