• Home
  • Search Results
  • Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency.

Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency.

Disease models & mechanisms (2013-11-26)
Peter J McGuire, Tatiana N Tarasenko, Tony Wang, Ezra Levy, Patricia M Zerfas, Thomas Moran, Hye Seung Lee, Brian J Bequette, George A Diaz
ABSTRACT

The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ammonia solution, 7 N in methanol
Sigma-Aldrich
Ammonia, anhydrous, ≥99.98%
Sigma-Aldrich
(±)-Propylene oxide, ReagentPlus®, ≥99%
Sigma-Aldrich
(±)-Propylene oxide, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
Ammonia solution, 0.4 M in THF
Supelco
(±)-Propylene oxide, analytical standard
Sigma-Aldrich
Ammonia solution, 0.4 M in dioxane
Sigma-Aldrich
Ammonia solution, 2.0 M in methanol
Sigma-Aldrich
Ammonia solution, 4 M in methanol
Sigma-Aldrich
Ammonia solution, 2.0 M in isopropanol
Sigma-Aldrich
Ammonia, puriss., anhydrous, ≥99.95%
Sigma-Aldrich
Ammonia-14N, 99.99 atom % 14N
Sigma-Aldrich
Ammonia, puriss., anhydrous, ≥99.9%