Introduction: This dissertation focuses on profiling the changes in metabolism that
occur as a result of hemorrhagic shock and traumatic injury as observed in urine obtained
from a porcine model. Hemorrhagic shock and traumatic injury are responsible for the
majority of deaths under the age of 44. A porcine model of hemorrhagic shock and
traumatic injury was used to examine changes in metabolism due to hemorrhagic shock
and traumatic injury. Changes in metabolism were hypothesized to be dependent upon
the metabolic state the animal occupies upon injury (fed or fasted). It was also
hypothesized that a metabolite or metabolites could serve as a marker of mortality.
Materials and Methods: Nuclear magnetic resonance (NMR) spectroscopy and
Chenomx software were used to generate individual profiles of metabolite concentrations
(the metabolome) for each urine sample obtained. Because hemorrhagic shock produces
drastic changes in urine concentration and large fluctuations in the concentrations of
endogenous metabolites in the urine, urine must be normalized to urine output to allow for accurate comparisons between urine samples. The urinary metabolome was analyzed
with partial least squares discriminant analysis (PLS-DA) and with a scale-free network.
Results: PLS-DA models showed that metabolites associated with respiration,
ischemia/reperfusion injury, and cell membrane damage were observed in the urine two
hours after the initiation of resuscitation. Other metabolites which may be associated
with injury sustained from surgical preparation were observed at 20 hours after the
initiation of resuscitation. The metabolites 1,6-Anhydro β-D-glucose and mannose were
associated with the metabolome of fed animals. The network analysis of the metabolome is reflective of the scale-invariant nature of metabolism. Respiratory metabolites were
separated by whether they are involved in aerobic or anaerobic respiration. Anaerobic
metabolites were also associated with markers of cell membrane rupture. Lactate,
pyruvate, 2-oxoglutarate, succinate, taurine, glycine, dimethylamine, and creatinine were
identified as well-connected hub metabolites in the network. No metabolites were
associated with survival alone.
Conclusions: The pathophysiology associated with hemorrhagic shock can be treated as
a scale invariant process particularly with respect to metabolism. Results from a
traditional metabolomics treatment of the data with PLS-DA models were congruent with
results from a scale-invariant, weakly modular network of the urinary metabolome.
Other samples obtained from these experiments (muscle, liver, and serum) could benefit
from a similar treatment. Additional work in (a) integrating the metabolomes of all four biological samples and (b) creating a physics-based theory of hemorrhagic shock may
provide important information about mortality and the propagation of injury.
University of Minnesota Ph.D. dissertation. December 2011. Major: Biophysical Sciences and Medical Physics. Advisors: E. Russel Ritenour and Bruce Hammer. 1 computer file (PDF); x, 251 pages, appendices A-B.
Lusczek, Elizabeth Rose.
Metabolic alterations associated with hemorrhagic shock and traumatic injury as measured in the urine..
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