title: Reduced activation of immunomodulatory transcription factors during positive end-expiratory pressure adjustment based on volume-dependent compliance in isolated perfused rabbit lungs.
abstract: BACKGROUND
  Repeated alveolar collapse and cyclic alveolar overdistension with associated activation of inflammatory signalling cascades contribute to ventilator-induced lung injury (VILI). The appropriate positive end-expiratory pressure (PEEP) which prevents or ameliorates VILI is unknown. In the isolated perfused lung, repeated adjustments of PEEP based on the continuously analysed intratidal compliance-volume curve have previously been shown to result in full end-expiratory alveolar recruitment and low risk of cyclic alveolar overdistension. Accordingly, we tested the hypothesis that such ventilatory management reduces intrapulmonary activation of the immunomodulatory transcription factors nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1) and cAMP-responsive element binding protein (CREB) which induce the expression of various chemokines and cytokines.
  
  
  METHODS
  Isolated perfused rabbit lungs were randomly allocated to one of three groups: zero end-expiratory pressure (ZEEP) to induce repeated alveolar collapse (n=6), high PEEP to induce cyclic alveolar overdistension (n=6) and repeated PEEP adjustments based on intratidal compliance-volume curve analysis by the slice method to minimize repeated alveolar collapse and overdistension (n=9). All lungs were ventilated with a tidal volume of 6 ml kg(-1) bodyweight for 120 min. Thereafter, activation of transcription factors NF-kappaB, AP-1 and CREB in lung tissue was analysed by electrophoretic mobility shift assay.
  
  
  RESULTS
  High PEEP was associated with the highest activation of NF-kappaB and AP-1 and repeated PEEP adjustments with the lowest activation when compared with the other two study groups (P<0.001). In contrast, activation of CREB did not differ between groups. Activated NF-kappaB and AP-1 protein complexes consisted mainly of the transactivators p50/p65 and c-Fos/Jun, respectively.
  
  
  CONCLUSIONS
  In isolated perfused rabbit lungs, repeated adjustments of PEEP based on the continuously analysed intratidal compliance-volume curve were associated with less activation of early steps of inflammatory signalling cascades than ventilation with ZEEP or high PEEP.
authors.affiliation: Department of Anaesthesiology and Critical Care Medicine, University Hospital, Hugstetterstrasse 55, 79106 Freiburg, Germany. edgar.kirchner@uni-freiburg.de
authors.forename: E A
authors.initials: EA
authors.lastname: Kirchner
authors.forename: G
authors.initials: G
authors.lastname: Mols
authors.forename: G
authors.initials: G
authors.lastname: Hermle
authors.forename: J D
authors.initials: JD
authors.lastname: Muehlschlegel
authors.forename: K K
authors.initials: KK
authors.lastname: Geiger
authors.forename: J
authors.initials: J
authors.lastname: Guttmann
authors.forename: H L
authors.initials: HL
authors.lastname: Pahl
mesh_terms: D000818:Animals; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008170:Lung Compliance / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011175:Positive-Pressure Respiration / Q000379:methods*; D011817:Rabbits; D015656:Respiratory Mechanics / Q000502:physiology; D013990:Tidal Volume; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator