{
  "abstract": "Background While delivery of supplemental oxygen is a life-saving therapy, exposure to high oxygen, called hyperoxia, leads to increased intensive care unit mortality. Hyperoxia induces oxidant-mediated acute lung injury (ALI) and pulmonary cell death, called hyperoxic ALI (HALI). Elucidating molecular mechanisms in HALI could identify therapeutic targets in ALI.Methods In the current study, we examined in vivo effects of HALI on Beclin-1 (BCN1), which regulates autophagy, and modulation of BCN1 by epidermal growth factor receptor (EGFR). Effects of HALI on BCN1 and autophagy were examined in mice with genetically decreased EGFR (EGFR Wa5/+). Wildtype (WT) and EGFRWa5/+ mice were exposed to 100% oxygen for 24–72 hours along with normoxia controls (eight groups; n=4–6/group), and analysis of pulmonary BCN1 and autophagy was completed.Results In WT, HALI led to increased BCN1 (59% increased total BCN1/β-Actin; p<0.01) in lung and alveolar epithelium (484% increased H-score; p<0.001). HALI led to decreased microtubule-associated protein 1B-light chain (LC3B)-II/-I ratios (43% decrease; p<0.05) and increased p62 (93% increase; p<0.05), suggesting reduced autophagic flux. In human alveolar type-II cells derived from induced pluripotent stem cells (AT2s iPSC), HALI caused increased LDH release (130% increase; p<0.0001) and decreased LC3B-II/-I ratios (32% decrease; p<0.05). We previously showed that EGFRWa5/+ mice are protected in HALI. In the current study, EGFRWa5/+ mice showed increased pulmonary BCN1 (122% increase; p<0.05), reduced phosphorylated-(p-)/total BCN1 (47% decrease; p<0.05) and decreased LC3B-II/-I ratios (70% decrease; p<0.01) in HALI compared with WT. In addition, wortmannin (1 mg/kg), which decreases BCN1-mediated autophagy, increased mortality in HALI compared with vehicle control (n=10/group; 18% decreased hours survived; p<0.001).Conclusions These data delineate a novel cell death pathway in HALI involving BCN1 and EGFR with therapeutic potential.",
  "authors": [
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, VA Connecticut Healthcare System, West Haven, Connecticut, USA",
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Zachary M Harris"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Asawari Korde"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Johad Khoury"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, VA Connecticut Healthcare System, West Haven, Connecticut, USA",
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Edward P Manning"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Gail Stanley"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA",
        "Griffin Hospital, Derby, Connecticut, USA"
      ],
      "name": "Yosep Shin"
    },
    {
      "affiliations": [
        "Yale University, New Haven, Connecticut, USA"
      ],
      "name": "Kennedy Mitchell"
    },
    {
      "affiliations": [
        "Yale University, New Haven, Connecticut, USA"
      ],
      "name": "Alexa von der Schulenburg"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Ying Sun"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Buqu Hu"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Hyeon Jun Shin"
    },
    {
      "affiliations": [
        "Division of Pulmonary Medicine, Mayo Clinic, Rochester, Minnesota, USA"
      ],
      "name": "John Joerns"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Brian Clark"
    },
    {
      "affiliations": [
        "The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA"
      ],
      "name": "Lindsey Placek"
    },
    {
      "affiliations": [
        "The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA"
      ],
      "name": "Derya Unutmaz"
    },
    {
      "affiliations": [
        "Department of Respiratory & Immunology, AstraZeneca PLC, Gaithersburg, Maryland, USA"
      ],
      "name": "Aigul Moldobaeva"
    },
    {
      "affiliations": [
        "Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine",
        "Department of Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA"
      ],
      "name": "Lokesh Sharma"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Maor Sauler"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Govindarajan Rajagopalan"
    },
    {
      "affiliations": [
        "Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Xuchen Zhang"
    },
    {
      "affiliations": [
        "Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA"
      ],
      "name": "He Wang"
    },
    {
      "affiliations": [
        "Department of Respiratory & Immunology, AstraZeneca PLC, Gaithersburg, Maryland, USA"
      ],
      "name": "Mahboobe Ghaedi"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Min-Jong Kang"
    },
    {
      "affiliations": [
        "Section of Pulmonary, Critical Care, and Sleep Medicine",
        "Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Jonathan L Koff"
    }
  ],
  "title": "Epidermal growth factor receptor regulates Beclin-1 in hyperoxic acute lung injury",
  "uid": "d56e6252-d752-5209-881c-b4062a82c64d"
}