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NASA NTRS1977

Some questions of space bioengineering

Zero-gravity offers selective effect on growth and metabolic activity unicellular organisms as well as unique opportunities in purification of organic compounds. These make it possible to consider the biosynthesis and recovery of certain metabolites economically feasible in space. Design, construction and operation of systems for the above mentioned purposes requires interdisciplinary actions within the scope of a new discipline: space bioengineering. The problems and perspectives of this discipline particularly in the application of bioreactor-recovery systems in space to manufacture metabolites of high economic and scientific value. Special attention is paid to pivotal factors such as various mass transport phenomena, contamination control, automatic control of optimum environment and synchronization of the operation of the biological (biosynthesis) and the physiochemical (recovery-purification) systems.

Nyiri, L. K.↗

NASA NTRS2011

Managing Toxicological Risks: The Legacy of Shuttle Operations

Space toxicology greatly matured as a result of research and operations associated with the Shuttle. Materials offgassing had been a manageable concern since the Apollo days, but we learned to pay careful attention to compounds that could escape containment, to combustion events, to toxic propellants, to overuse of utility compounds, and to microbial and human metabolites. We also learned that flying real-time hardware to monitor air pollutants was a pathway with unanticipated speed bumps. Each new orbiter was tested for any excess offgassing products that could pollute the air during flight. In the late 1990s toxicologists and safety experts developed a 5-level toxicity rating system to guide containment of toxic compounds. This system is now in use aboard the International Space Station (ISS). Several combustion events during Shuttle Mir and also during Shuttle free-flight impelled toxicologists to identify hardware capable of monitoring toxic products; however, rapid adaptation of the hardware for the unique conditions of spaceflight caused unexpected missteps. Current and planned combustion analyzers would be useful to commercial partners that wish to manage the risk of health effects from thermal events. Propellants received special attention during the Shuttle program because of the possibility of bringing them into the habitable volume on extravehicular activity suits. Monitors for the airlocks were developed to mitigate this risk. Utility materials, such as lubricants, posed limited toxicological problems because water was not recovered. One clearly documented case of microbial metabolites polluting the Shuttle atmosphere was noted, and this has implications for commercial flights and control of microbes. Finally, carbon dioxide, the major human metabolite, episodically presented air quality problems aboard Shuttle, especially when nominal air flows were obstructed. Commercial vehicles must maintain robust air circulation given the anticipated high density of human occupants.

James, John T.↗

NASA NTRS1999

A Quantitative Study of Oxygen as a Metabolic Regulator

An acute reduction in oxygen (O2) delivery to a tissue is generally associated with a decrease in phosphocreatine, increases in ADP, NADH/NAD, and inorganic phosphate, increased rates of glycolysis and lactate production, and reduced rates of pyruvate and fatty acid oxidation. However, given the complexity of the human bioenergetic system and its components, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in tissue O2 availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study, we extend a previously developed mathematical model of human bioenergetics to provide a physicochemical framework that permits quantitative understanding of O2 as a metabolic regulator. Specifically, the enhancement permits studying the effects of variations in tissue oxygenation and in parameters controlling the rate of cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The whole body is described as a bioenergetic system consisting of metabolically distinct tissue/organ subsystems that exchange materials with the blood. In order to study the dynamic response of each subsystem to stimuli, we solve the ordinary differential equations describing the temporal evolution of metabolite levels, given the initial concentrations. The solver used in the present study is the packaged code LSODE, as implemented in the NASA Lewis kinetics and sensitivity analysis code, LSENS. A major advantage of LSENS is the efficient procedures supporting systematic sensitivity analysis, which provides the basic methods for studying parameter sensitivities (i.e., changes in model behavior due to parameter variation). Sensitivity analysis establishes relationships between model predictions and problem parameters (i.e., initial concentrations, rate coefficients, etc). It helps determine the effects of uncertainties or changes in these input parameters on the predictions, which ultimately are compared with experimental observations in order to validate the model. Sensitivity analysis can identify parameters that must be determined accurately because of their large effect on the model predictions and parameters that need not be known with great precision because they have little or no effect on the solution. This capability may prove to be important in optimizing the design of experiments, thereby reducing the use of animals. This approach can be applied to study the metabolic effects of reduced oxygen delivery to cardiac muscle due to local myocardial ischemia and the effects of acute hypoxia on brain metabolism. Other important applications of sensitivity analysis include identification of quantitatively relevant pathways and biochemical species within an overall mechanism, when examining the effects of a genetic anomaly or pathological state on energetic system components and whole system behavior.

Radhakrishnan, Krishnan↗

NASA NTRS1988

The stimulation of arachidonic acid metabolism in human platelets by hydrodynamic stresses

The effects of stimulating human platelets by thrombin and by hydrodynamic stresses on the platelets' arachidonic acid metabolism were investigated using (1-C-14)-arachidonic acid label and a specially designed viscometer that ensured laminar shear flow with a nearly uniform shear rate throughout the flow region. It was found that platelets activated by thrombin formed principally thromboxane A2, 12-hydroxy 5,8,10-heptadecatrienoic acid and 12-hydroxy 5,8,10,14-eicosatetraenoic acid (12-HETE). On the other hand, platelets activated by shear, formed only 12-HETE (although arachidonic acid metabolism was stimulated); no cyclooxygenase metabolites were detected. Results indicate that platelets may greatly increase their 12-HETE production when activated by passage through a high-stress region of the circulation, such as an atherosclerotic stenosis.

Rajagopalan, Sridhar↗

NASA NTRS2007

Effects of Hind Limb Unloading on Pharmacokinetics of Procainamide in Mice

The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in space. It is prudent to expect that low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration. Among the medications of special interest are the cardiovascular drugs, especially the antiarrhythmic agents. In this study we used hind limb unloaded (HLU) mice as a model to investigate possible changes in the PK of a common antiarrhythmic drug procainamide (PA). Prior to drug administration the experimental animals were tail suspended for 24 hours and the control animals were kept free. PA (150-250 mg per kg) was given orally by a gavage procedure. After that the experimental mice were kept suspended for additional 1, 2, 3 and 6 hours. At these time points the serum concentration of PA and N-acetyl-procainamide (NAPA), an active metabolite which is formed by N-acetyltransferase in the liver, were measured by the fluorescence polarization immunoassay (FPIA) on the AxSYM autoanalyzer (Abbott Laboratories, Abbott Park, IL). The serum level of PA in HLU mice at 1 hour after administration was almost 40% lower than in controls. At 2-3 hours the difference still maintained, however, it was not statistically significant; at 6 hours no difference was detected. The level of NAPA in HLU mice was slightly lower at 1 and 2 hours but the difference did not reach statistical significance. The estimated PA half-life time in HLU mice was almost 55% longer than in control animals. These results confirm that hind limb unloading and related hemodynamic changes significantly alter the PK of PA. The effects are most likely primarily associated with a decrease in the drug absorption, especially within the first two hours after administration. At the same time prolongation of the PA half-life time in the HLU mice points towards slower drug elimination from the circulation.

Risin, Semyon A.↗