title: High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling.
abstract: BACKGROUND
  Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury.
  
  
  METHODS
  Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated.
  
  
  RESULTS
  S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation.
  
  
  CONCLUSIONS
  S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands. Ilse.Kuipers@amc.nl
authors.forename: Maria T
authors.initials: MT
authors.lastname: Kuipers
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Hamid
authors.initials: H
authors.lastname: Aslami
authors.forename: Geartsje
authors.initials: G
authors.lastname: Jongsma
authors.forename: Elske
authors.initials: E
authors.lastname: van den Berg
authors.forename: Alexander P J
authors.initials: AP
authors.lastname: Vlaar
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Juffermans
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D055397:Ventilator-Induced Lung Injury / Q000503:physiopathology*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4