title: Dynamic model of eicosanoid production with special reference to non-steroidal anti-inflammatory drug-triggered hypersensitivity.
abstract: The authors developed a mathematical model of arachidonic acid (AA) degradation to prostaglandins (PGs) and leukotrienes (LTs), which are implicated in the processes of inflammation and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). The model focuses on two PGs (PGE2 and PGD2) and one LT (LTC4), their % increases and their ratios. Results are compared with experimental studies obtained from non-asthmatics (NAs), and asthmatics tolerant (ATA) or intolerant (AIA) to aspirin. Simulations are carried out for predefined model populations NA, ATA and three AIA, based on the differences of two enzymes, PG E synthase and/or LTC4-synthase in two states, that is, no-inflammation and inflammation. Their model reveals that the model population with concomitant malfunctions in both enzymes is the most sensitive to NSAIDs, since the duration and the capacity for bronchoconstriction risk are highest after simulated oral dosing of indomethacin. Furthermore, inflammation prolongs the duration of the bronchoconstriction risk in all AIA model populations, and the sensitivity analysis reveals multiple possible scenarios leading to hypersensitivity, especially if inflammatory processes affect the expression of multiple enzymes of the AA metabolic pathway. Their model estimates the expected fold-changes in enzyme activities and gives valuable information for further targeted transcriptomic/proteomic and metabolomic studies.
authors.affiliation: Faculty of Health Sciences, University of Maribor, Žitna ulica 15, 2000 Maribor, Slovenia. ales.fajmut@um.si.
authors.forename: Aleš
authors.initials: A
authors.lastname: Fajmut
authors.affiliation: Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Koroška cesta 160, 2000 Maribor, Slovenia.
authors.forename: Tadej
authors.initials: T
authors.lastname: Emeršič
authors.affiliation: Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Dobovišek
authors.affiliation: Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Koroška cesta 160, 2000 Maribor, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Antić
authors.affiliation: Allergie und Intoleranzlabor, Medizinisch Klinik III, Friedrich-Alexander-Universität Erlangen-Nürnberg, Glückstraße 4a, 91054 Erlangen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schäfer
authors.affiliation: Jožef Stefan Institute, Jamova ulica 39, 1000 Ljubljana, Slovenia.
authors.forename: Milan
authors.initials: M
authors.lastname: Brumen
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D019295:Computational Biology; D003198:Computer Simulation; D004342:Drug Hypersensitivity / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D018448:Models, Immunological
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids