DescriptionChronic inflammation and increased oxidative burden lay the foundation for endothelial dysfunction, which itself is the eminent precursor to a host of chronic inflammatory related conditions. The endothelium has many important homeostatic functions, including regulating vascular tone, promoting an antithrombotic state, redistributing of blood flow, and mediating the immune response. Nitric oxide (NO) has been recognized as the most important vasoactive molecule produced by the endothelium. Both its production and its ability to carry out targeted signaling effects are critical to the endothelium’s overall maintenance of vascular health. However, due to the chemical nature of NO it is susceptible to rapid oxidation and subsequent decrease in effectiveness. Therefore, NO signaling capabilities are reliant on the balance between its rate of production and its rate of oxidation, a factor heavily influenced by the oxidative state of the vascular environment.
The overall goal of this dissertation work is to further investigate the disparaging relationship between chronic inflammation and NO bioavailability using different models of inflammation and oxidative burden. This goal is carried out through three primary projects; i) the construction of a novel web-based application used to accurately assess NO quantities in biological samples (termed PeakAUC, Chapter2); ii) examination of sex specific differences in overnight NO oxidation in subjects with obstructive-sleep apnea (Chapter 4); and iii) characterization of the inflammatory profiles (immunophenotyping) in military Veterans with unexplained respiratory symptoms and this phenotype relationship to NO production and multi-system physiological function (Chapter 3 and Chapter 5).
While a strong association between NO oxidation and inflammatory and/or oxidative burden is described, more work is needed to further uncover the exact intermediate mechanisms involved. I demonstrate the association between increased oxidative events and increased overnight NO oxidation in subjects with OSA – and demonstrate this relationship is dependent on sex. Additionally, I offer insight into the possible mechanisms underlying unexplained respiratory symptoms in military Veterans. Notably, an increased inflammatory phenotype is associated with sub-clinical pulmonary dysfunction, reduced exercise capacity, and low levels of NO. This work seeks to advance our knowledge of the critical role of NO bioavailability in the development of progression of chronic inflammatory illnesses.