{
  "abstract": "Rationale Hyperoxia may be associated with adverse ICU outcomes but despite numerous large-scale randomised clinical trials (RCTs) there is ongoing lack of consensus regarding optimal oxygenation strategies. Importantly, detailed mechanistic understanding of the potential pro-inflammatory effects of hyperoxia remain to be defined.Objective To test the hypothesis that hyperoxia will modify pulmonary and systemic inflammation and cellular injury in the setting of inhaled lipopolysaccharide (LPS) challenge.Methods In this single-centre, randomised, double-blind, allocation-concealed, placebo-controlled trial ( NCT05414370), healthy non-smoking adult volunteers (<45 years of age) were randomised (1:1) to receive hyperoxia administered via high-flow nasal oxygen delivery system (FiO2 1.0, 60L/min flow rate) or synthetic medical air for a duration of 6-hours. Bronchoalveolar lavage (BAL) was performed at 6-hours following inhalation of 50µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of pulmonary and systemic inflammation, as well as epithelial cell injury. Untargeted metabolomic and lipidomic profiling of BAL fluid and plasma was conducted using liquid chromatography-tandem mass spectrometry to investigate oxidative stress. Transcriptomic analysis was performed on whole blood.Results Between January 2023 and March 2024, a total of 22 participants were recruited and completed all study procedures. Exposure to hyperoxia for a duration of 6-hours did not significantly increase the pre-specified primary outcome measure BAL IL-8 (hyperoxia 375.7 pg/ml; placebo 331.9 pg/ml; p=0.33). There were no between-group differences in BAL cytokines or plasma markers of systemic inflammation. However, untargeted metabolomics analysis found hyperoxia was associated with differentially altered BAL metabolites including upregulation of reduced glutathione (p=0.02), glycerophosphoglycerol (p=0.04) and downregulation of cysteinylglycine disulfide (p=0.04). Furthermore, hyperoxia induced distinct transcriptional response at 24h with 247 DEGs (p<0.05). Enrichment analysis indicated activation of platelet-related pathways and ECM-receptor interactions.Conclusions In a human model of pulmonary inflammation induced by inhaled lipopolysaccharide, 6 hours of hyperoxia does not accentuate the innate pulmonary or systemic inflammatory response nor cause overt tissue damage.",
  "authors": [
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK",
        "Mater Hospital Belfast, Belfast Health and Social Care Trust, Belfast, UK"
      ],
      "name": "DA Linden"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "D Dorrian"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "M Glenn"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "K Welzenbach"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "MJ Rowland"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "M Yang"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "L Klein"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "E Randazzo"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "M Sindelar"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "J Schlotterbeck"
    },
    {
      "affiliations": [
        "Novartis Biomedical research, CH-4002, Basel, Switzerland"
      ],
      "name": "A Cattini"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "S Tandel"
    },
    {
      "affiliations": [
        "NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK"
      ],
      "name": "A Dushianthan"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "MC McKelvey"
    },
    {
      "affiliations": [
        "Mater Hospital Belfast, Belfast Health and Social Care Trust, Belfast, UK"
      ],
      "name": "M Bailey"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "J Conlon"
    },
    {
      "affiliations": [
        "Mater Hospital Belfast, Belfast Health and Social Care Trust, Belfast, UK"
      ],
      "name": "D Moore"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, Northern Ireland Clinical Research Facility, Queen’s University Belfast, UK"
      ],
      "name": "S Carr"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, Northern Ireland Clinical Research Facility, Queen’s University Belfast, UK"
      ],
      "name": "JM Bradley"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "D Simpson"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "CC Taggart"
    },
    {
      "affiliations": [
        "Mater Hospital Belfast, Belfast Health and Social Care Trust, Belfast, UK"
      ],
      "name": "JC Kidney"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK"
      ],
      "name": "CM O’Kane"
    },
    {
      "affiliations": [
        "Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK",
        "Regional Intensive Care Unit, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK"
      ],
      "name": "DF McAuley"
    }
  ],
  "title": "S4 Effects of hyperoxia on pulmonary inflammation and organ injury in a human in vivo model (HIPI): a randomised, double-blind, placebo-controlled trial",
  "uid": "a771aabd-9863-5dcd-bc8e-2e208cc46bc0"
}