The Effect of Critical Illness on Gene Expression in the Lungs

Abstract

Gene expression can change rapidly in response to a stimuli such as critical illness. Yet, few studies have investigated the gene changes in organs during critical illness, largely because these cannot be taken from live human patients. It is known that in critically ill patients, the gut becomes under-perfused, resulting in ischemic injury and a loss in barrier function. It is believed pro-inflammatory cytokines and toxic mediators released by the gut are carried to key organs, including the heart and lungs through gut-lymph. These toxic factors may act to propagate acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS), the leading cause of death in critically ill patients. I have profiled the gene changes in the lungs of three rat models of critical illness; acute pancreatitis (AP), gut-ischemia reperfusion (Gut I/R) and sepsis. These varied disease states represent some of the wide-ranging aetiologies that can lead to critical illness in humans. The potential therapeutic effects of mesenteric lymph drainage has also been assessed through its impact on lung gene expression. The lungs were chosen as the organ system of choice to study as they are typically the organ system that fails first in patients who progress to MODS. Changes in the gene expression in lung tissues were determined by transcriptome microarrays, then select candidate genes were validated by TaqMan qRT-PCR. As an additional study, the candidate genes were then assessed in an ex vivo model of ventilator induced lung injury (VILI), with and without treatment of Pep5. The information gleaned from this study will provide insights into the rapid gene expression changes in lungs following induction of critical illness. It will also assess the effect of mesenteric lymph drainage on these genes, with the hopes of identifying potentially therapeutic effects. In addition, the effectiveness of a novel treatment option in Pep5 will be assessed in models of lung damage.