Lung ischaemia-reperfusion induced gene expression

Abstract

Objectives: Pulmonary dysfunction following lung ischaemia-reperfusion is a well-known phenomenon, which may contribute to post-cardiac surgical morbidity. The process is associated with pulmonary inflammatory response and cellular apoptosis. Early molecular mechanisms leading to such lung injury remain largely unknown. We examined whether lung ischaemia and reperfusion cause significant expression changes in numerous genes in the lungs involved in pulmonary apoptosis and other cellular processes by using oligonucleotide microarrays in an experimental model of rodent lung ischaemia-reperfusion injury.

Methods: Sprague-Dawley rodents (n=5 in each group) were anaesthetised and underwent controlled ventilation, with varying durations of warm lung ischaemia (60 and 90 min) followed by a short reperfusion period. The right middle lobe of the lung was harvested. Gene expression changes in the lungs were analysed by rodent DNA microarray chips, and reverse transcription polymerase chain reaction (RT-PCR) performed to validate changes in gene expression.

Results: Significant expression changes, with reference to false discovery rate (FDR) controls, were detected in over 80 genes following controlled lung ventilation, and more than 50 were up-regulated more than 2-fold. Lung ischaemia-reperfusion caused expression changes in over 50 additional genes, including many novel genes not previously associated with lung ischaemia-reperfusion. Up-regulated genes identified include those associated with apoptosis, inflammation and cell-cycle control.

Conclusions: Large numbers of genes relating to cell metabolism, transcription control, inflammation and apoptosis were significantly up- and down-regulated following controlled ventilation and early lung ischaemia-reperfusion, consistent with previous studies. In addition, novel genes related to lung injury were identified. These genetic signatures provide new insights into early molecular mechanisms of ischaemia-reperfusion lung injury and help refine therapeutic strategies to lessen pulmonary dysfunction following cardiac surgery.