title: Toll-like receptor 4-myeloid differentiation factor 88 signaling contributes to ventilator-induced lung injury in mice.
abstract: BACKGROUND
  The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood.
  
  
  METHODS
  Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels.
  
  
  RESULTS
  Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV.
  
  
  CONCLUSIONS
  TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Su
authors.forename: Xuebin
authors.initials: X
authors.lastname: Yan
authors.forename: Karla
authors.initials: K
authors.lastname: Wasserloos
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: Zhao-Qian
authors.initials: ZQ
authors.lastname: Liu
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D013990:Tidal Volume / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000473:pathology*
chemical_list: D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4