IngentaConnect Reduced activation of immunomodulatory transcription factors duri...

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-

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

Document Type: Research article

DOI: 10.1093/bja/aei078

Affiliations: 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

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$40.19 plus tax Refund Policy

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