{
  "abstract": "Introduction Critically ill patients commonly develop acquired neutrophil dysfunction, which increases susceptibility to intensive care unit-acquired infection (ICU-AI). This study aimed to assess whether interferon gamma (IFN-γ) can restore function in dysfunctional neutrophils from critically ill patients and to uncover potential underlying mechanisms.Methods This was an observational cohort study. Neutrophils were isolated from whole blood donated by critically ill patients (n=31) in four separate teaching hospital intensive care units (ICUs). Neutrophils were subsequently treated with recombinant human IFN-γ or vehicle for 1 hour following either Fc gamma receptor (FcγR) blockade, selective inhibition of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ) or vehicle control for 30 min. Neutrophil phagocytosis, bacterial killing, superoxide generation, phagocytic receptor expression and small Rho GTPase activity were assessed. Neutrophil dysfunction was defined as <50% of cells ingesting 2 or more zymosan particles in a phagocytosis assay.Results IFN-γ significantly improved phagocytosis (control 36.5%, IFN-γ 56.0%), bacterial killing (control 31.6%, IFN-γ 82.1%) and superoxide generation (2.8-fold increase relative to control) in dysfunctional neutrophils. IFN-γ also increased the activity of the small GTPases, Rac and Cdc42 (2.4-fold and 1.5-fold increase relative to control, respectively) in dysfunctional neutrophils. Selective inhibition of PI3K-γ prevented the IFN-γ-mediated improvement of phagocytosis (IFN-γ 62.5%, with inhibitor 27.9%), bacterial killing (IFN-γ 82.1%, with inhibitor 30.5%) and superoxide generation (IFN-γ 2.8-fold change relative to control, 0.7 with inhibitor). The IFN-γ-mediated improvement of bacterial killing in dysfunctional neutrophils was also prevented by FcγR blockade (IFN-γ 82.1%, FcγR inhibition 28.7%).Conclusions In critically ill patients with known acquired neutrophil dysfunction, ex vivo application of IFN-γ consistently improved a range of neutrophil effector functions.",
  "authors": [
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Cameron J Lake"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Jonathan Scott"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Marie-Hélène Ruchaud-Sparagano"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "John H Thompson"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Fiona Dewar"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Polina Yarova"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Respiratory Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Wendy Funston"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Respiratory Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Richard CH Davidson"
    },
    {
      "affiliations": [
        "Haematology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Kathryn M Musgrave"
    },
    {
      "affiliations": [
        "Anaesthesia and Critical Care, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Stephen E Wright"
    },
    {
      "affiliations": [
        "Anaesthesia and Critical Care, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Ian Clement"
    },
    {
      "affiliations": [
        "Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK"
      ],
      "name": "Alistair I Roy"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Respiratory Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Wezi Sendama"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Department of Paediatric Otolaryngology, Great North Children’s Hospital, Newcastle Upon Tyne, UK"
      ],
      "name": "Jason Powell"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Daniel Brooks"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Chung Mun Alice Lin"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Kristen Davies"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Anaesthesia and Critical Care, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Thomas P Hellyer"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK"
      ],
      "name": "Anthony J Rostron"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Respiratory Medicine, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "A John Simpson"
    }
  ],
  "title": "Interferon gamma applied ex vivo restores function to neutrophils from critically ill patients",
  "uid": "e48dcffa-352c-5fdf-9de5-4274cafdd894"
}