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

Autor: Michael F. Beers, Gladys G. Lawrence, Jason D. Christie, Jennifer Pogoriler, Edward E. Morrisey, Y. Suzuki, William J. Zacharias, Edward Cantu, David M. Chenoweth, Dolinay Tamas, Chanat Aonbangkhen, Alec M. Stablow, Susan S. Margulies
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Respiratory Research, Vol 19, Iss 1, Pp 1-14 (2018)
Respiratory Research
Popis: 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje