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 (10 ng/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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 275-281 |
| Number of pages | 7 |
| Journal | Nitric Oxide - Biology and Chemistry |
| Volume | 25 |
| Issue number | 3 |
| DOIs | |
| State | Published - Oct 30 2011 |
Fingerprint
Keywords
- Arginase
- l-Arginine
- Nitric oxide synthase
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Clinical Biochemistry
- Cancer Research
Cite this
Modeling gas phase nitric oxide release in lung epithelial cells. / Jiang, Jingjing; George, Steven.
In: Nitric Oxide - Biology and Chemistry, Vol. 25, No. 3, 30.10.2011, p. 275-281.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modeling gas phase nitric oxide release in lung epithelial cells
AU - Jiang, Jingjing
AU - George, Steven
PY - 2011/10/30
Y1 - 2011/10/30
N2 - 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 (10 ng/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.
AB - 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 (10 ng/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.
KW - Arginase
KW - l-Arginine
KW - Nitric oxide synthase
UR - http://www.scopus.com/inward/record.url?scp=80053926448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053926448&partnerID=8YFLogxK
U2 - 10.1016/j.niox.2011.04.010
DO - 10.1016/j.niox.2011.04.010
M3 - Article
C2 - 21550413
AN - SCOPUS:80053926448
VL - 25
SP - 275
EP - 281
JO - Nitric Oxide - Biology and Chemistry
JF - Nitric Oxide - Biology and Chemistry
SN - 1089-8603
IS - 3
ER -