Genetic and Epigenetic Regulation of NAMPT/PBEF Expression in Human Lung Endothelium

Hypoxemia, pulmonary edema and persistent inflammation are cardinal features of acute respiratory distress syndrome (ARDS) and patients suffer from respiratory failure resulting from flooding of the alveolar space. Mechanical ventilation remains the only therapeutic option available to support respiration. However, excessive mechanical forces and tidal volumes characteristic of mechanical ventilation results in structural and physiological injury to the lung tissue which is exacerbated with prior insults. With effective pharmacotherapies yet to emerge novel strategies are required for alleviation of this morbid syndrome affecting over 200,000 people with high mortality rates. Orthologous gene expression arrays utilizing multispecies pre-clinical models of lung injury identified NAMPT a novel cytozyme significantly upregulated with chemoattractant and inflammation inducing properties and localized to the lung endothelium, epithelium and leukocytes. However, the mechanisms of its upregulation remain less understood. In this thesis, I have studied and elucidated the biochemical, genetic and epigenetic factors that drive NAMPT gene expression in the human lung endothelium. Our results demonstrate that excessive mechanical stress drives NAMPT gene expression further influencing ARDS susceptibiity associated genetic variants in a STAT5 dependent manner. The upregulation occurred via epigenetic mechanisms targeting the NAMPT 5’ UTR and 3’UTR. Further extracellular NAMPT altered the histone H3K9 acetylation profile in a TLR4 dependent manner. These results shed light on the influences of NAMPT transcription in VILI and provide novel targets for development of therapeutic strategies to alleviate ventilator-induced lung injury. Further, the influence of SNP’s on transcription of NAMPT would be a valuable resource for personalized medicine.