Wollbold2014 - Effects of reactive oxygen species

  public model
Short description
Wollbold2014 - Effects of reactive oxygen species

This model is described in the article:

Wollbold J, Jaster R, Müller S, Rateitschak K, Wolkenhauer O.
BMC Syst Biol 2014 Sep; 8(1): 101

Abstract:

BackgroundRecent 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.ResultsSimulations 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.ConclusionsThe 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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L3V1)
Related Publication
  • Anti-inflammatory effects of reactive oxygen species - a multi-valued logical model validated by formal concept analysis.
  • Wollbold J, Jaster R, Müller S, Rateitschak K, Wolkenhauer O.
  • BMC Syst Biol 2014; 8: 101 , 0/ 2014 , Volume 8 , pages: 101
  • 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.
Contributors
Johannes Wollbold

Metadata information

is
BioModels Database MODEL1407230001
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology necrotic cell death
Human Disease Ontology acute pancreatitis
occursIn
Brenda Tissue Ontology pancreatic acinar cell
Curation status
Non-curated
Original model(s)
http://www.sbi.uni-rostock.de/resources/software/multi-valued-logic-and-fca/
  • Model originally submitted by : Johannes Wollbold
  • Submitted: Jul 23, 2014 9:25:47 PM
  • Last Modified: Oct 17, 2014 2:30:15 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Oct 17, 2014 2:30:15 PM
    • Submitted by: Johannes Wollbold
    • With comment: Current version of Wollbold2014 - Effects of reactive oxygen species
  • Version: 1 public model Download this version
    • Submitted on: Jul 23, 2014 9:25:47 PM
    • Submitted by: Johannes Wollbold
    • With comment: Original import of MODEL1407230001.xml.origin