Carbon monoxide (CO) is an odorless, colorless, tasteless gas that binds to hemoglobin with high affinity. This property underlies the use of low doses of CO to determine hemoglobin mass (MHb) in the fields of clinical and sports medicine. However, hemoglobin bound to CO is unable to transport oxygen and exposure to high CO concentrations is a significant environmental and occupational health concern. These contrasting aspects of CO—clinically useful in low doses but potentially lethal in higher doses—mandates a need for a quantitative understanding of the temporal profiles of the uptake and distribution of CO in the human body. In this dissertation I have (i) used a mathematical model to analyze CO-rebreathing techniques used to estimate total hemoglobin mass and proposed a CO-rebreathing procedure to estimate hemoglobin mass with low errors, (ii) enhanced and validated a multicompartment model to estimate O2, CO and CO2 tensions, bicarbonate levels, pH levels, blood carboxyhemoglobin (HbCO) levels, and carboxymyoglobin (MbCO) levels in all the vascular (arterial, mixed venous and vascular subcompartments of the tissues) and tissue (brain, heart and skeletal muscle) compartments of the model in normoxia, hypoxia, CO hypoxia, hyperoxia, isocapnic hyperoxia and hyperbaric oxygen, and (iii) used this developed mathematical model to propose a treatment to improve O2 delivery and CO removal by comparing O2 and CO levels during different treatment protocols administered for otherwise-healthy CO-poisoned subjects.

[Truncated abstract] Therapeutic Radiation has been used for the treatment of cancer and other diseases for nearly a century. Over the past 20 years, Hyperbaric Oxygen Treatment (HBOT) has been used to assist wound healing in the prevention and treatment of the more severe complications associated with the side effects of Therapeutic Radiation Treatment (TRT). The use of HBOT is based on the premise that increased oxygen tissue tension aids wound healing by increasing the hypoxic gradient and stimulating angiogenesis and fibroblast differentiation. As it takes up to 6 months for a hypoxic state to develop in treated tissue, following radiation treatment, current recommendations for HBOT state that it is not effective until after this time. During this 6 month period, immediately following TRT, many specialized tissues in or adjacent to the field of irradiation, such as salivary glands and bone, are damaged due to a progressive thickening of arteries and fibrosis, and these tissues are never replaced. Currently, HBOT is used to treat the complications of TRT, but it would be far better if they could be prevented . . . In summary, this experimental model has fulfilled its prime objective of demonstrating that HBOT is effective in reducing the long-term side effects of therapeutic radiation treatment in normal tissue, when given one week after the completion of the radiation treatment and statistically disproves the Null Hypothesis that there is no difference in the incidence of postoperative complications or morbidity of TRT when 20 intermittent daily HBOT are started one week after completion of TRT. This project provides an extensive description of the histological process and also proposes a hypothesis for the molecular events that may be taking place.

<p>Magnetic resonance spectroscopy (MRS) is a non-invasive diagnostic technique that provides unique information about the biochemical composition of the human body. By excluding the overwhelming signals from water and fat, clinically relevant biomarkers such as lactate, N-acetyl aspartate, choline, creatine, glutamate/glutamine (Glx), gamma-aminobutyric acid (GABA), glutathione, and myoinositol can be reliably quantified. MRS has diverse applications in investigating the metabolic window of a wide range of biochemical processes. </p> <p>Here, we have utilized MRS to better understand chemical changes associated with neurological disorders and treatment response. We have investigated neurometabolic imbalances in brain regions related to post-traumatic stress disorder (PTSD). MRS was applied to better understand the neurobiological processes of hyperbaric oxygen therapy in military veterans with clinically diagnosed traumatic brain injury and/or PTSD.</p>

The caudal solitary complex (cSC) is a cardiorespiratory integrative center in the dorsal medulla oblongata that plays a vital role in the central CO2-chemoreceptive network. Neurons in this area respond to hypercapnic acidosis (HA) by a depolarization of the membrane potential and increase in firing rate, however a definitive mechanism for this response remains unknown. Likewise, CO2-chemoreceptive neurons in the cSC respond to hyperoxia in a similar fashion, but via a free radical mediated mechanism. It remains unknown if the response to increased pO2 is merely an increase in redox signaling, or if it’s the result of a pathological state of redox stress. Importantly, free radical production is known to be stimulated by increasing pO2, and can be exacerbated downstream by the addition of CO2 and its subsequent acidosis. Conditions of hyperoxia in combination with HA can therefore become detrimental in several scenarios, including O2 toxicity seizures in divers and stranded submariners, as well as in cases of ischemia-reperfusion injury and sleep apneas. As such, we sought to not only determine how O2 and CO2 interact to affect cellular excitability in the cSC, but also if these cells exhibited increases in redox signaling and/or stress. We employed sharp-electrode intracellular electrophysiology to study whole-cell electrical responses to varied combinations of hyperoxia (0.4 0.95/1.95 ATA O2) and HA (0.05 0.1 ATA CO2). Additionally, we used fluorescence microscopy under similar conditions to study changes in the production rates of various free radicals, including superoxide (˙O2-), nitric oxide (˙NO), and a downstream aggregate pool of CO2/H+-dependent reactive oxygen and nitrogen species (RONS). Finally, we used several colorimetric assays to measure markers of oxidative and nitrosative stress, including malondialdehyde, 3-nitrotyrosine, and protein carbonyls. Our hypothesis for these experiments was that hyperoxia and HA alone could produce effects, but would be more pronounced when used together. As such, we saw that ~89% of cells tested that were sensitive to both hyperoxia and HA showed larger firing rate responses to HA during an increased background O2 (0.9 and/or 1.9 ATA) after showing a smaller response or no response to HA during control levels O2 (0.4 ATA). Additionally, we noted that the rate of ˙O2- fluorescence increased in response to hyperoxia, but only during pharmacological inhibition of its reactions with ˙NO and SOD. Likewise, the rate of ˙NO fluorescence increased during hyperoxia compared to control O2, but only during pharmacological scavenging of ˙O2-. Downstream, our aggregate pool of RONS showed increased rates of fluorescence during both hyperoxia alone and HA in control O2, however the most prominent increases were seen during hypercapnic hyperoxia. Finally, no significant effects were seen when probing for markers of redox stress in response to hyperoxia and hypercapnic hyperoxia. Overall, these results suggest that the increased excitability seen in cSC neurons during hypercapnic hyperoxia is the result of physiological redox signaling rather than pathological redox stress. Further research needs to be done to determine how this redox mechanism is specifically resulting in increased cellular excitability.