Nitric oxide and the lung : Effects of spaceflight and hypergravity

Nitric oxide (NO) is an important signal molecule in the body, in particular in the cardiovascular system. This highly reactive molecule is difficult to detect in tissues, but in gas-filled cavities such as the airways it can be detected in part per billion amounts. This thesis explores the possible use of NO to monitor or modify lung function when healthy subjects are exposed to reduced and increased gravity, and to reduced ambient pressures. In the first part of this thesis, the Russian procedure for extravehicular activities (EVA) is studied during ground simulations and aboard the international space station. EVA includes decompression and it was concluded that weightlessness appears to be protective against decompression-related disorders. Therefore, the hypothesis that exhaled NO could be used to detect decompression bubbles in the lung circulation could not be substantiated. It was also concluded that lowered ambient pressure reduces the normal level of exhaled nitric oxide; this is important knowledge if exhaled NO is to be used as a measure of lung health. In the second and third parts of this thesis the influence of gravity-induced alterations of the distributions of blood, gas and tissue in the lungs on exhaled nitric oxide, was assessed. By exposing healthy subjects to hypergravity and microgravity (weightlessness), it was concluded that hypergravity-induced impaired matching of blood and gas in the lungs slows blood uptake of locally produced nitric oxide, resulting in increased levels of exhaled nitric oxide. Also lung deformation in hypergravity decreases blood uptake and hence increases exhaled levels. In support of the above, it was found that improved matching in microgravity decreases exhaled levels of exhaled nitric oxide. Additionally, in the use of experimental hypergravity data and mathematical simulations, it can be expressed in quantitative terms how the increased levels of exhaled nitric oxide found in hypergravity were caused by decreased contact surface between gas and blood and by narrowing of small peripheral airways. Exposure of the healthy lungs to hypergravity can simulate key components of acute respiratory distress syndrome, a severe type of lung insufficiency. In the last part of this thesis, the role of the hypoxic pulmonary vasoconstriction in these disorders was assessed by means of hypergravity-induced hypoxemia and pharmacological interventions. No protective role of the vasoconstriction could be seen on hypergravityinduced hypoxia in five times normal gravity. However, recent preliminary data from a follow-up study suggest a protective role at lower hypergravity levels when the lung deformation is less pronounced