Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis
Date
2014-09
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: Recent findings suggest that in pancreatic acinar cells stimulated with bile acid, a pro-apoptotic effect of
reactive oxygen species (ROS) dominates their effect on necrosis and spreading of inflammation. The first effect
presumably occurs via cytochrome C release from the inner mitochondrial membrane. A pro-necrotic effect – similar to
the one of Ca2+ – can be strong opening of mitochondrial pores leading to breakdown of the membrane potential,
ATP depletion, sustained Ca2+ increase and premature activation of digestive enzymes. To explain published data and
to understand ROS effects during the onset of acute pancreatitis, a model using multi-valued logic is constructed.
Formal concept analysis (FCA) is used to validate the model against data as well as to analyze and visualize rules that
capture the dynamics.
Results: Simulations for two different levels of bile stimulation and for inhibition or addition of antioxidants reproduce
the qualitative behaviour shown in the experiments. Based on reported differences of ROS production and of ROS
induced pore opening, the model predicts a more uniform apoptosis/necrosis ratio for higher and lower bile
stimulation in liver cells than in pancreatic acinar cells. FCA confirms that essential dynamical features of the data are
captured by the model. For instance, high necrosis always occurs together with at least a medium level of apoptosis. At
the same time, FCA helps to reveal subtle differences between data and simulations. The FCA visualization underlines
the protective role of ROS against necrosis.
Conclusions: The analysis of the model demonstrates how ROS and decreased antioxidant levels contribute to
apoptosis. Studying the induction of necrosis via a sustained Ca2+ increase, we implemented the commonly accepted
hypothesis of ATP depletion after strong bile stimulation. Using an alternative model, we demonstrate that this process
is not necessary to generate the dynamics of the measured variables. Opening of plasma membrane channels could
also lead to a prolonged increase of Ca2+ and to necrosis. Finally, the analysis of the model suggests a direct
experimental testing for the model-based hypothesis of a self-enhancing cycle of cytochrome C release and ROS
production by interruption of the mitochondrial electron transport chain.
Description
CITATION: Wollbold, J. et al. 2015. Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis. BMC Systems Biology, 8:101, doi:10.1186/s12918-014-0101-7.
The original publication is available at http://bmcsystbiol.biomedcentral.com
The original publication is available at http://bmcsystbiol.biomedcentral.com
Keywords
Acute pancreatitis, Mitochondria, Reactive oxygen species, Anti-inflammatory agents, Apoptosis, Necrosis
Citation
Wollbold, J. et al. 2015. Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis. BMC Systems Biology, 8:101, doi:10.1186/s12918-014-0101-7.