title: Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.
abstract: Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolinay
authors.affiliation: 2 Department of Biostatistics, Epidemiology and Informatics, and.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: 2 Department of Biostatistics, Epidemiology and Informatics, and.
authors.forename: Maya
authors.initials: M
authors.lastname: Shumyatcher
authors.affiliation: 3 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gladys Gray
authors.initials: GG
authors.lastname: Lawrence
authors.affiliation: 3 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan S
authors.identifier: 0000-0002-3615-7902
authors.initials: SS
authors.lastname: Margulies
mesh_terms: D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D016923:Cell Death; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011654:Pulmonary Edema / Q000188:drug therapy / Q000209:etiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D056811:Unfolded Protein Response; D055397:Ventilator-Induced Lung Injury / Q000503:physiopathology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
chemical_list: D051701:Activating Transcription Factor 4; D000225:Adenine; D016207:Cytokines; D007211:Indoles; D011480:Protease Inhibitors; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat
keywords: alveolar epithelium; integrated stress response; ventilator-induced lung injury