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

• Type of Material: Article
• Authors: Tamas Dolinay, University of Pennsylvania; Chanat Aonbangkhen, University of Pennsylvania; William Zacharias, University of Pennsylvania; Edward Cantu, University of Pennsylvania; Jennifer Pogoriler, Children's Hospital of Philadelphia; Alec Stablow, University of Pennsylvania; Gladys G. Lawrence, University of Pennsylvania; Yoshikazu Suzuki, University of Pennsylvania; David M. Chenoweth, University of Pennsylvania; Edward Morrisey, University of Pennsylvania; Jason D. Christie, University of Pennsylvania; Michael F. Beers, University of Pennsylvania; Susan Margulies, Emory University
• Language: English
• Date: 2018-08-22
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12931-018-0856-2
• Title of Journal or Parent Work: Respiratory Research
• ISSN: 1465-9921
• Volume: 19
• Issue: 1
• Start Page: 157
• End Page: 157
• Grant/Funding Information: Funding: University of Pennsylvania Internal Funds to SSM and NIH 5T32HL007586 to TD.
• Keywords: Science & Technology; BERLIN DEFINITION; Life Sciences & Biomedicine; INTEGRATED STRESS-RESPONSE; GENE-EXPRESSION; EIF2-ALPHA KINASE; TRANSLATIONAL REGULATION; Protein kinase R-like endoplasmic reticulum kinase; ALVEOLAR EPITHELIAL-CELLS; PERK; ER STRESS; RESPIRATORY-DISTRESS-SYNDROME; Respiratory System; Ventilator-induced lung injury; Alveolar epithelium; IN-VITRO
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.