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Publication Detail

Title: Protein kinase R-like endoplasmatic reticulum kinase is a mediator of stretch in ventilator-induced lung injury.

Authors: Dolinay, Tamás; Aonbangkhen, Chanat; Zacharias, William; Cantu, Edward; Pogoriler, Jennifer; Stablow, Alec; Lawrence, Gladys G; Suzuki, Yoshikazu; Chenoweth, David M; Morrisey, Edward; Christie, Jason D; Beers, Michael F; Margulies, Susan S

Published In Respir Res, (2018 Aug 22)

Abstract: Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential causes of ARDS; however, alveolar injury associated with mechanical ventilation, termed ventilator-induced lung injury (VILI), remains a well-recognized contributor. It is thus critical to understand the mechanism of VILI. Based on our published preliminary data, we hypothesized that the endoplasmic reticulum (ER) stress response molecule Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) plays a role in transmitting mechanosensory signals the alveolar epithelium.ER stress signal responses to mechanical stretch were studied in ex-vivo ventilated pig lungs. To explore the effect of PERK inhibition on VILI, we ventilated live rats and compared lung injury parameters to non-ventilated controls. The effect of stretch-induced epithelial ER Ca2+ signaling on PERK was studied in stretched alveolar epithelial monolayers. To confirm the activation of PERK in human disease, ER stress signaling was compared between ARDS and non-ARDS lungs.Our studies revealed increased PERK-specific ER stress signaling in response to overstretch. PERK inhibition resulted in dose-dependent improvement of alveolar inflammation and permeability. Our data indicate that stretch-induced epithelial ER Ca2+ release is an activator of PERK. Experiments with human lung tissue confirmed PERK activation by ARDS.Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.

PubMed ID: 30134920 Exiting the NIEHS site

MeSH Terms: Adult; Aged; Animals; Endoplasmic Reticulum Stress/physiology*; Female; Humans; Lung/metabolism*; Lung/pathology; Male; Middle Aged; Pulmonary Stretch Receptors/metabolism*; Pulmonary Stretch Receptors/pathology; Rats; Rats, Sprague-Dawley; Respiratory Mucosa/metabolism; Respiratory Mucosa/pathology; Swine; Ventilator-Induced Lung Injury/metabolism*; Ventilator-Induced Lung Injury/pathology; eIF-2 Kinase/physiology*

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