S63 Comparison of mechanisms of repair and regeneration in experimental models of acute respiratory distress syndrome

Abstract

Background The acute respiratory distress syndrome (ARDS) is a clinical condition with multiple aetiologies. Previous work has presented two relevant, distinct animal models of ARDS. A murine model of aspiration using acid, in which the lung injury begins to resolve after 48 hours, and another of infection using LPS, that continues to deteriorate. It has been suggested that alveolar epithelial regeneration is implicated in disease progression to different extents between the models. We hypothesised that the wnt and retinoic acid pathways are involved in regeneration and resolution of these murine models of ARDS, and that there is greater activation of these pathways in the aspiration compared to the infection model. Currently, management of ARDS is irrespective of lung injury aetiology, and these mechanisms may prove relevant for pathway modulation for future therapy. Methods Mice were administered either 25 µl intratracheal 0.1 M hydrochloric acid (aspiration model, n=5), 25 µg LPS (infection model, n=6) or sham treated (controls, n=6) and sacrificed at 48 hours. Lung tissue was homogenised. mRNA and protein levels of regenerative pathway genes were quantified, through reverse-transcription polymerase chain reaction and Western blotting. Results Significant upregulation of all 9 regenerative genes studied was seen in the acid model compared to controls. Rac-2 mRNA (wnt pathways) was the only regenerative gene in the LPS-injured mice to show a significant upregulation compared to controls (67.39±25.73 vs 0.32±0.13 ΔCTx1010p Conclusions There is significant upregulation of wnt and retinoic acid pathways in the lung tissue of these murine models of ADRS, suggesting greater regeneration in the acid (aspiration) model. Two genes (Daam-2 and RBP-1) showed significant inter-model differences, as did β-catenin protein expression. Further investigation of these pathways is warranted to see if modulation of these regenerative pathways may prove beneficial in treating different ARDS aetiologies.