title: Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury.
abstract: Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.
  
  
  
  To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.
  
  
  
  Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.
  
  
  
  In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.
  
  
  
  These results indicate that lung-marginated intravascular monocytes are retained as a 'passenger' leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Kate Colette
authors.initials: KC
authors.lastname: Tatham
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Kieran Patrick
authors.initials: KP
authors.lastname: O'Dea
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.|Departments of Anaesthesia and Cardiothoracic Transplantation, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, Middlesex, UK.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Romano
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Hannah Elizabeth
authors.initials: HE
authors.lastname: Donaldson
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakabayashi
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Brijesh Vipin
authors.initials: BV
authors.lastname: Patel
authors.affiliation: Departments of Anaesthesia and Cardiothoracic Transplantation, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, Middlesex, UK.
authors.forename: Louit
authors.initials: L
authors.lastname: Thakuria
authors.affiliation: Departments of Anaesthesia and Cardiothoracic Transplantation, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, Middlesex, UK.
authors.forename: Andre Rudiger
authors.initials: AR
authors.lastname: Simon
authors.affiliation: Faculty of Medicine, National Heart & Lung Institute, Imperial College, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UK.
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.|Departments of Anaesthesia and Cardiothoracic Transplantation, Harefield Hospital, Royal Brompton and Harefield NHS Foundation Trust, Harefield, Middlesex, UK.
authors.forename: Nandor
authors.initials: N
authors.lastname: Marczin
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D008168:Lung / Q000503:physiopathology; D016040:Lung Transplantation / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011014:Pneumonia / Q000503:physiopathology; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D014019:Tissue Donors
chemical_list: D016207:Cytokines
keywords: Innate Immunity; Lung Transplantation; Macrophage Biology