Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence



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This research has not been peer-reviewed. It is a preliminary report that should not be regarded as conclusive, guide clinical practice or health-related behaviour, or be reported in news media as established information.

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

Author list:


  1. University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
  2. Barts Cancer Research Institute, Queen Mary University of London, London, United Kingdom
  3. Intensive Care Unit, Royal Infirmary of Edinburgh, NHS Lothian
  4. Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh
  5. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
  6. Department of Respiratory Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  7. Roslin Institute, University of Edinburgh, Edinburgh, UK
  8. Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
  9. Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  10. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  11. The Francis Crick Institute, London, United Kingdom


Ananda S. Mirchandani1*, Stephen J. Jenkins1†, Calum C.Bain1†, Hannah Lawson2, Patricia Coelho1, Fiona Murphy1, David Griffith1, Ailiang Zhang1, Manuel A. Sanchez-Garcia1, Leila Reyes1, Tyler Morrison1, Simone Arienti1, Pranvera Sadiku1, Emily R. Watts1, Rebecca. S. Dickinson1, Sarah Clark3, Tony Ly4, David Lewis4, Van Kelly4, Christos Spanos4, Kathryn M. Musgrave5,6, Liam Delaney1, Isla Harper1, Jonathan Scott5, Nicholas J. Parkinson7, Anthony J. Rostron5, Kenneth J Baillie7,3, Sara Clohisey7, Clare Pridans1, Lara Campana8, Philip Starkey-Lewis8, A John Simpson5, David Dockrell1, 10, Jurgen Schwarze1, Nikhil Hirani1, Peter J. Ratcliffe9,10,11, Christopher W. Pugh9, Kamil Kranc2, Stuart J. Forbes1,8, Moira K. Whyte1, Sarah R. Walmsley1.