title: Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin.
abstract: BACKGROUND
  Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia.
  
  
  METHODS
  We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation.
  
  
  RESULTS
  In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1-3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p < 0.01; prevention of pulmonary restriction) and against VILI-induced liver and gut injury in pneumonia (91% reduction of AST levels p < 0.05, 96% reduction of alanine aminotransaminase (ALT) levels p < 0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut).
  
  
  CONCLUSIONS
  MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia.
authors.forename: Holger C
authors.initials: HC
authors.lastname: Müller-Redetzky
authors.forename: Daniel
authors.initials: D
authors.lastname: Will
authors.forename: Katharina
authors.initials: K
authors.lastname: Hellwig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Uwe
authors.initials: U
authors.lastname: Pfeil
authors.forename: Renate
authors.initials: R
authors.lastname: Paddenberg
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D053607:Adrenomedullin / Q000627:therapeutic use*; D000818:Animals; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000473:pathology / Q000517:prevention & control*; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000473:pathology / Q000517:prevention & control*; D055397:Ventilator-Induced Lung Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D001993:Bronchodilator Agents; D053607:Adrenomedullin
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