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

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          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 Ca 2+ 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 Ca 2+ 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.

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          Most cited references36

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          Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome.

          Tidal volume and plateau pressure limitation decreases mortality in acute respiratory distress syndrome. Computed tomography demonstrated a small, normally aerated compartment on the top of poorly aerated and nonaerated compartments that may be hyperinflated by tidal inflation. We hypothesized that despite tidal volume and plateau pressure limitation, patients with a larger nonaerated compartment are exposed to tidal hyperinflation of the normally aerated compartment. Pulmonary computed tomography at end-expiration and end-inspiration was obtained in 30 patients ventilated with a low tidal volume (6 ml/kg predicted body weight). Cluster analysis identified 20 patients in whom tidal inflation occurred largely in the normally aerated compartment (69.9 +/- 6.9%; "more protected"), and 10 patients in whom tidal inflation occurred largely within the hyperinflated compartments (63.0 +/- 12.7%; "less protected"). The nonaerated compartment was smaller and the normally aerated compartment was larger in the more protected patients than in the less protected patients (p = 0.01). Pulmonary cytokines were lower in the more protected patients than in the less protected patients (p < 0.05). Ventilator-free days were 7 +/- 8 and 1 +/- 2 d in the more protected and less protected patients, respectively (p = 0.01). Plateau pressure ranged between 25 and 26 cm H(2)O in the more protected patients and between 28 and 30 cm H(2)O in the less protected patients (p = 0.006). Limiting tidal volume to 6 ml/kg predicted body weight and plateau pressure to 30 cm H(2)O may not be sufficient in patients characterized by a larger nonaerated compartment.
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            The PERK Eukaryotic Initiation Factor 2α Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas

            Phosphorylation of eukaryotic initiation factor 2α (eIF-2α) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2α (eIF-2α[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2α. Among the four eIF-2α kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2α[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk −/− mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk −/− mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
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              Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

              Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampal-dependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head trauma-induced chronic cognitive deficits.
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                Author and article information

                Contributors
                tdolinay@mednet.ucla.edu
                chanat@fas.harvard.edu
                willam.zacharias@uphs.upenn.edu
                Edward.cantuIII@uphas.upenn.edu
                pogorilerj@email.chop.edu
                stablowa@seas.upenn.edu
                ggb@seas.upenn.edu
                yoshikazu.suzuki@uphs.upenn.edu
                dcheno@sas.upenn.edu
                emorrise@upenn.edu
                jchristi@upenn.edu
                mfbeers@pennmedicine.upenn.edu
                404.385.5038 , susan.margulies@gatech.edu
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                22 August 2018
                22 August 2018
                2018
                : 19
                : 157
                Affiliations
                [1 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, , University of Pennsylvania, ; 3400 Spruce St, Philadelphia, PA 19104 USA
                [2 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Medicine, Division of Pulmonary and Critical Care Medicine, , University of California Los Angeles, ; 10833 Le Conte Ave, Los Angeles, CA 90095 USA
                [3 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Chemistry University of Pennsylvania, ; 231 S 34th St, Philadelphia, PA 19104 USA
                [4 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Surgery, , University of Pennsylvania, ; 3400 Spruce St, Philadelphia, PA 19104 USA
                [5 ]ISNI 0000 0001 0680 8770, GRID grid.239552.a, Department of Pathology, Children’s Hospital of Philadelphia, ; 3400 S 34th St, Philadelphia, PA 19104 USA
                [6 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Bioengineering, , University of Pennsylvania, ; 210 South 33rd St, Suite 240 Skirkanich Hall Philadelphia, Philadelphia, PA 19104 USA
                [7 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Medicine, Division of Cardiovascular Medicine, , University of Pennsylvania, ; 3400 Spruce St, Philadelphia, PA 19104 USA
                [8 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University, , University School of Medicine, ; U.A. Whitaker Building, 313 Ferst Drive, Suite 2116, Atlanta, GA 30332-0535 USA
                Author information
                http://orcid.org/0000-0002-3615-7902
                Article
                856
                10.1186/s12931-018-0856-2
                6106739
                30134920
                d1ff1271-e520-4562-aed3-e7d61900c868
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 April 2018
                : 6 August 2018
                Funding
                Funded by: University of Pennsylvania Internal Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: 5T32HL007586
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Respiratory medicine
                ventilator-induced lung injury,protein kinase r-like endoplasmic reticulum kinase,alveolar epithelium

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