title: Mechanical ventilation in healthy mice induces reversible pulmonary and systemic cytokine elevation with preserved alveolar integrity: an in vivo model using clinical relevant ventilation settings.
abstract: BACKGROUND
  Mechanical ventilation (MV) may activate the innate immune system, causing the release of cytokines. The resulting proinflammatory state is a risk factor for ventilator-induced lung injury. Cytokine increase results from direct cellular injury but may also result from cyclic stretch alone as demonstrated in vitro: mechanotransduction. To study mechanotransduction in vivo, the authors used an animal MV model with clinically relevant ventilator settings, avoiding alveolar damage.
  
  
  METHODS
  Healthy C57BL6 mice (n = 82) were ventilated (tidal volume, 8 ml/kg; positive end-expiratory pressure, 4 cm H2O; fraction of inspired oxygen, 0.4) for 30, 60, 120, and 240 min. Assigned animals were allowed to recover for 2 days after MV. Both pulmonary tissue and plasma interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor alpha, IL-6, IL-10, and keratinocyte-derived chemokine levels were measured. Histopathologic appearance of lung tissue was analyzed by light microscopy and electron microscopy.
  
  
  RESULTS
  In lung tissue, all measured cytokines and keratinocyte-derived chemokine levels increased progressively with MV duration. Light microscopy showed increased leukocyte influx but no signs of alveolar leakage or albumin deposition. Electron microscopy revealed intact epithelial cell and basement membranes with sporadically minimal signs of partial endothelial detachment. In plasma, increased levels of IL-1alpha, tumor necrosis factor alpha, IL-6, and keratinocyte-derived chemokine were measured after MV. In the recovery animals, cytokine levels had normalized and no histologic alterations could be found.
  
  
  CONCLUSIONS
  Mechanical ventilation induces reversible cytokine increase and leukocyte influx with preserved tissue integrity. This model offers opportunities to study the pathophysiologic mechanisms behind ventilator-induced lung injury and the contribution of MV to the "multiple-hit" concept.
authors.affiliation: Department of Anesthesiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.vaneker@anes.umcn.nl
authors.forename: Michiel
authors.initials: M
authors.lastname: Vaneker
authors.forename: Feico J
authors.initials: FJ
authors.lastname: Halbertsma
authors.forename: Jan
authors.initials: J
authors.lastname: van Egmond
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Henry B
authors.initials: HB
authors.lastname: Dijkman
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Snijdelaar
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joosten
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Scheffer
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001794:Blood Pressure; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D007378:Interleukins / Q000097:blood; D015603:Keratinocytes; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron / Q000379:methods; D023421:Models, Animal; D011650:Pulmonary Alveoli / Q000503:physiopathology*; D012016:Reference Values; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018925:Chemokines; D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha