title: Lung-marginated monocytes modulate pulmonary microvascular injury during early endotoxemia.
abstract: BACKGROUND
  The role of monocytes in acute endotoxemia has been ascribed to systemic release of mediators within the central circulation. Little is known about the potential role of "marginated" monocytes in regulating microvascular inflammatory signaling.
  
  
  OBJECTIVE
  To investigate whether lung-marginated monocytes can locally activate pulmonary endothelial cells through cell contact-dependent interactions in early endotoxemia.
  
  
  METHODS
  Mice were challenged with LPS to produce acute endotoxemia and pulmonary vascular injury. Adoptive transfer of ex vivo LPS-stimulated donor leukocytes to recipient mice was also performed to evaluate cell-associated inflammatory signaling between monocytes and endothelial cells within the lung. Cell suspensions from excised lungs were analyzed by flow cytometry for expression of tumor necrosis factor alpha (TNF-alpha) on monocytes and cell adhesion molecules on endothelial cells.
  
  
  RESULTS
  Substantial numbers of monocytes rapidly marginated to the lungs after endotoxin challenge in mice, and lung-marginated monocytes expressed significantly higher levels of membrane TNF than circulating monocytes, due to higher TNF production by the marginated cells. Injection of activated wild-type donor leukocytes to wild-type or TNF receptor double knockout recipients demonstrated that lung-marginated monocytes can induce TNF-dependent upregulation of adhesion molecules on pulmonary endothelial cells. Injection of activated donor leukocytes from TNF knock-in mice that express uncleavable mutant membrane TNF also induced adhesion molecule upregulation in wild-type recipients without a systemic soluble TNF release.
  
  
  CONCLUSIONS
  These results reveal a previously unacknowledged role for lung-marginated monocytes in early endotoxemia, exerting local, cell-associated TNF signaling within the pulmonary microcirculation, contributing to the evolution of pulmonary vascular injury.
authors.affiliation: Department of Anaesthetics and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Young
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: James L
authors.initials: JL
authors.lastname: Robotham
authors.forename: Fionula M
authors.initials: FM
authors.lastname: Brennan
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000502:physiology; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4