Fig. 7

The hypothetical role of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) signaling in VILI. Mechanical overstretch activates PERK endoplasmic reticulum (ER) stress signaling independent of Inositol Requiring Enzyme (IRE)-1α and Activating Transcription Factor (ATF)-6 in the alveoli. Stretch-mediated ER Ca²⁺ efflux contributes to PERK activation, which in turn increases Integrated Stress Response (ISR) by phosphorylating eukaryotic Initiation Factor (eIF)-2α and facilitating the transcription of ATF4 and CCAAT/Enhancer-binding Protein Homologous Protein (CHOP). Significant increases in CHOP expression result in pro-injury gene transcription leading to alveolar epithelial barrier dysfunction and inflammation. ISR-mediated Growth Arrest and DNA Damage-inducible Protein (GADD)-34 dephosphorylates eIF2α to prevent perpetual ISR activation. Arrow = activation, x = no effect, | = inhibition