title: Dissociation of inflammatory mediators and function: experimental lung injury in nonpulmonary sepsis.
abstract: BACKGROUND
  Sepsis is a common indication for mechanical ventilation, which, with higher tidal volume, can cause ventilator-associated lung injury. Inflammatory mediators in the plasma or bronchoalveolar fluid are sometimes proposed as biomarkers in ICU patients.
  
  
  OBJECTIVE
  To test the hypothesis that "priming" with subthreshold sepsis in a clinically relevant model would worsen lung function, increase ventilator-induced mediator production, and differentially impact systemic vs. pulmonary mediator levels. The model used was cecal ligation and perforation modified so that alone it caused lung inflammatory responses but not injury.
  
  
  RESULTS
  Anesthetized mice were randomized to cecal ligation and perforation (vs. sham) with or without dexamethasone and 6 hrs later further randomized to: 1) sham, nonventilated, saline; 2) cecal ligation and perforation, nonventilated, saline; 3) cecal ligation and perforation, nonventilated, dexamethasone; 4) sham, high tidal volume, saline; 5) sham, high tidal volume, dexamethasone; 6) cecal ligation and perforation, high tidal volume, saline; or 7) cecal ligation and perforation, high tidal volume, dexamethasone. Mediators associated with sepsis and lung injury (cytokines: interleukin-6, tumor necrosis factor-α; chemokine: keratinocyte stimulating factor) were measured in the plasma and the bronchoalveolar lavage, and lung function (compliance, oxygenation, alveolar protein leak) assessed. High tidal volume and cecal ligation and perforation increased individual bronchoalveolar lavage and plasma mediators; high tidal volume but not cecal ligation and perforation impaired lung function. Priming of high tidal volume by cecal ligation and perforation intensified plasma and bronchoalveolar lavage mediators; the plasma (but not the bronchoalveolar lavage) mediators were inhibited by dexamethasone pretreatment.
  
  
  CONCLUSIONS
  Mediator-but not functional-responses to high tidal volume are augmented by subthreshold sepsis priming. There is important discordance among systemic and pulmonary mediators, physiologic function, and response to corticosteroids; thus, mediator levels may be incomplete surrogates for measures of lung injury or response to therapy in the context of systemic sepsis.
authors.affiliation: Program in Physiology and Experimental Medicine, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Satoko
authors.initials: S
authors.lastname: Uematsu
authors.forename: Doreen
authors.initials: D
authors.lastname: Engelberts
authors.forename: Vanya
authors.initials: V
authors.lastname: Peltekova
authors.forename: Gail
authors.initials: G
authors.lastname: Otulakowski
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000276:immunology* / Q000628:therapy*; D013990:Tidal Volume; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000276:immunology*
chemical_list: D015415:Biomarkers; D018925:Chemokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha