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BJA Advance Access published online on January 21, 2005
British Journal of Anaesthesia, doi:10.1093/bja/aei078
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005
Accepted December 13, 2004

Laboratory Investigation

Reduced activation of immunomodulatory transcription factors during positive end-expiratory pressure adjustment based on volume-dependent compliance in isolated perfused rabbit lungs

E. A. Kirchner 1*, G. Mols 1, G. Hermle 1, J. D. Muehlschlegel 2, K. K. Geiger 1, J. Guttmann 1, and H. L. Pahl 1

1 Department of Anaesthesiology and Critical Care Medicine, University Hospital, Hugstetterstraße 55, 79106 Freiburg, Germany
2 Department of Anaesthesiology, University of Florida, PO Box 100254, Gainesville, FL 32610-0254, USA

* To whom correspondence should be addressed.
E. A. Kirchner, E-mail: edgar.kirchner{at}uni-freiburg.de


  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 {kappa}B (NF-{kappa}B), 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-{kappa}B, 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-{kappa}B 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-{kappa}B 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.

Keywords: biochemistry, transcription factors, activator protein-1; biochemistry, transcription factors, cAMP responsive element binding protein; biochemistry, transcription factors, nuclear factor-{kappa}B; lung, model; model, rabbit; ventilation, positive end-expiratory pressure.
(G. Hermle is sadly deceased)
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