title: Modeling gas phase nitric oxide release in lung epithelial cells.
abstract: Nitric oxide (NO) is present in exhaled breath and is generally considered to be a noninvasive marker of airway inflammation, and is thus of particular relevance to monitoring asthma. NO is produced when L-arginine is converted to L-citrulline by NO synthase (NOS); however, L-arginine is also the substrate for arginase and both enzymes are upregulated in asthma. Recent reports have speculated that enhanced expression of one or both enzymes could lead to a limitation in substrate availability, and hence impact downstream targets or markers such as exhaled NO. The non-linear nature and vastly different kinetics of the enzymes make predictions difficult, particularly over the wide range of enzyme activity between baseline and inflammation. In this study, we developed a steady state model of L-arginine transmembrane transport, NO production, diffusion, and gas phase NO release from lung epithelial cells. We validated our model with experimental results of gas phase NO release and intracellular l-arginine concentration in A549 cells, and then performed a sensitivity analysis to determine relative impact of each enzyme on NO production. Our model predicts intracellular L-arginine and gas phase NO release over a wide range of initial extracellular L-arginine concentrations following stimulation with cytomix (10ng/ml TNF-α, IL-1β, and INF-γ). Relative sensitivity analysis demonstrates that enhanced arginase activity has little impact on l-arginine bioavailability for NOS. In addition, NOS activity is the dominant parameter which impacts gas phase NO release.
authors.affiliation: Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jiang
authors.forename: Steven C
authors.initials: SC
authors.lastname: George
mesh_terms: D001249:Asthma / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005740:Gases / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D005740:Gases; D009569:Nitric Oxide