A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model

2007 ◽  
Vol 102 (1) ◽  
pp. 417-425 ◽  
Author(s):  
Peter Condorelli ◽  
Hye-Won Shin ◽  
Anna S. Aledia ◽  
Philip E. Silkoff ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Diffusion Model ◽  
Healthy Subjects ◽  
Elimination Rate ◽  
Compartment Model ◽  
No Production ◽  
Constant Flow ◽  
Axial Diffusion ◽  
Common Technique ◽  
Airway Tree

The most common technique employed to describe pulmonary gas exchange of nitric oxide (NO) combines multiple constant flow exhalations with a two-compartment model (2CM) that neglects 1) the trumpet shape (increasing surface area per unit volume) of the airway tree and 2) gas phase axial diffusion of NO. However, recent evidence suggests that these features of the lungs are important determinants of NO exchange. The goal of this study is to present an algorithm that characterizes NO exchange using multiple constant flow exhalations and a model that considers the trumpet shape of the airway tree and axial diffusion (model TMAD). Solution of the diffusion equation for the TMAD for exhalation flows >100 ml/s can be reduced to the same linear relationship between the NO elimination rate and the flow; however, the interpretation of the slope and the intercept depend on the model. We tested the TMAD in healthy subjects ( n = 8) using commonly used and easily performed exhalation flows (100, 150, 200, and 250 ml/s). Compared with the 2CM, estimates (mean ± SD) from the TMAD for the maximum airway flux are statistically higher ( J′awNO = 770 ± 470 compared with 440 ± 270 pl/s), whereas estimates for the steady-state alveolar concentration are statistically lower (CANO = 0.66 ± 0.98 compared with 1.2 ± 0.80 parts/billion). Furthermore, CANO from the TMAD is not different from zero. We conclude that proximal (airways) NO production is larger than previously predicted with the 2CM and that peripheral (respiratory bronchioles and alveoli) NO is near zero in healthy subjects.

Endothelial microparticles increase in mitral valve disease and impair mitral valve endothelial function

2013 ◽  
Vol 304 (7) ◽  
pp. E695-E702 ◽  
Author(s):  
Hong-Bo Ci ◽  
Zhi-Jun Ou ◽  
Feng-Jun Chang ◽  
Dong-Hong Liu ◽  
Guo-Wei He ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Mitral Valve ◽  
Mitral Regurgitation ◽  
Mitral Valve Disease ◽  
Healthy Subjects ◽  
Heat Shock Protein 90 ◽  
Valve Disease ◽  
No Production ◽  
Endothelial Microparticles

Mitral valve endothelial cells are important for maintaining lifelong mitral valve integrity and function. Plasma endothelial microparticles (EMPs) increased in various pathological conditions related to activation of endothelial cells. However, whether EMPs will increase in mitral valve disease and their relationship remains unclear. Here, 81 patients with mitral valve disease and 45 healthy subjects were analyzed for the generation of EMPs by flow cytometry. Human mitral valve endothelial cells (HMVECs) were treated with EMPs. The phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), the association of eNOS and heat shock protein 90 (HSP90), and the generation of nitric oxide (NO) and superoxide anion (O2˙−) were measured. EMPs were increased significantly in patients with mitral valve disease compared with those in healthy subjects. EMPs were negatively correlated with mitral valve area in patients with isolated mitral stenosis. EMPs were significantly higher in the group with severe mitral regurgitation than those in the group with mild and moderate mitral regurgitation. Furthermore, EMPs were decreased dramatically in both Akt and eNOS phosphorylation and the association of HSP90 with eNOS in HMVECs. EMPs decreased NO production but increased O2˙− generation in HMVECs. Our data demonstrated that EMPs were significantly increased in patients with mitral valve disease. The increase of EMPs can in turn impair HMVEC function by inhibiting the Akt/eNOS-HSP90 signaling pathway. These findings suggest that EMPs may be a therapeutic target for mitral valve disease.

A two-compartment model of pulmonary nitric oxide exchange dynamics

1998 ◽  
Vol 85 (2) ◽  
pp. 653-666 ◽  
Author(s):  
Nikolaos M. Tsoukias ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Elimination Rate ◽  
Compartment Model ◽  
Phase Iii ◽  
Exhaled Breath ◽  
Dynamic Relationship ◽  
Exhaled No ◽  
Two Compartment Model ◽  
Conducting Airways ◽  
The Relationship

The relatively recent detection of nitric oxide (NO) in the exhaled breath has prompted a great deal of experimentation in an effort to understand the pulmonary exchange dynamics. There has been very little progress in theoretical studies to assist in the interpretation of the experimental results. We have developed a two-compartment model of the lungs in an effort to explain several fundamental experimental observations. The model consists of a nonexpansile compartment representing the conducting airways and an expansile compartment representing the alveolar region of the lungs. Each compartment is surrounded by a layer of tissue that is capable of producing and consuming NO. Beyond the tissue barrier in each compartment is a layer of blood representing the bronchial circulation or the pulmonary circulation, which are both considered an infinite sink for NO. All parameters were estimated from data in the literature, including the production rates of NO in the tissue layers, which were estimated from experimental plots of the elimination rate of NO at end exhalation (ENO) vs. the exhalation flow rate (V˙E). The model is able to simulate the shape of the NO exhalation profile and to successfully simulate the following experimental features of endogenous NO exchange: 1) an inverse relationship between exhaled NO concentration and V˙E, 2) the dynamic relationship between the phase III slope andV˙E, and 3) the positive relationship between ENO andV˙E. The model predicts that these relationships can be explained by significant contributions of NO in the exhaled breath from the nonexpansile airways and the expansile alveoli. In addition, the model predicts that the relationship between ENO and V˙E can be used as an index of the relative contributions of the airways and the alveoli to exhaled NO.

Temporal nitric oxide dynamics in the paranasal sinuses during humming

2005 ◽  
Vol 98 (6) ◽  
pp. 2064-2071 ◽  
Author(s):  
Lars Menzel ◽  
Alexander Hess ◽  
Wilhelm Bloch ◽  
Olaf Michel ◽  
Klaus-Dieter Schuster ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Time Constant ◽  
Paranasal Sinuses ◽  
Compartment Model ◽  
Resonance Spectroscopy ◽  
No Production ◽  
No Emission ◽  
Experimental Conditions ◽  
Experimental Part ◽  
Three Compartment Model

In this study, the temporal shape of voice-induced nitric oxide (NO) signals in exhaled air has been investigated in eight healthy individuals by means of laser magnetic resonance spectroscopy. The results of the experimental part have been compared with calculated signals obtained by using a simple one-compartment model of the paranasal sinuses. In the experimental part, a rapidly increasing NO concentration has been found when the subjects started humming. After reaching a maximum, the emission starts to decrease with the shape of an exponential decay and finally reaches a constant level. The time constant of this decay (NO washout) is 3.0 ± 1.2 s. The peak height of the NO emission during humming increases when the time between two humming processes increases. When no voice-induced NO emission takes place, the NO concentration in the paranasal sinuses rebuilds again to a maximum concentration. The typical time constant for the NO recovery is 4.5 ± 3.2 min. A three-compartment model defining exactly the geometry and anatomy of the paranasal sinuses has been developed that is based on three main assumptions of the NO dynamics: 1) constant NO production of the epithelium in the sinuses; 2) the rate of the chemical reaction of NO with the epithelium of the paranasal sinuses is proportional to the NO concentration; and 3) the emission of NO from the sinuses (volume/s) is proportional to the NO concentration. It is shown that the three-compartment model under the experimental conditions can be reduced to a one-compartment model, which describes the complete temporal behavior of the NO exchange.

Impact of axial diffusion on nitric oxide exchange in the lungs

2002 ◽  
Vol 93 (6) ◽  
pp. 2070-2080 ◽  
Author(s):  
Hye-Won Shin ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Longitudinal Distribution ◽  
No Production ◽  
Small Airways ◽  
Diffusing Capacity ◽  
Alveolar Region ◽  
Axial Diffusion ◽  
Maximum Flux ◽  
Exhaled No ◽  
The Impact

Nitric oxide (NO) appears in the exhaled breath and is a potentially important clinical marker. The accepted model of NO gas exchange includes two compartments, representing the airway and alveolar region of the lungs, but neglects axial diffusion. We incorporated axial diffusion into a one-dimensional trumpet model of the lungs to assess the impact on NO exchange dynamics, particularly the impact on the estimation of flow-independent NO exchange parameters such as the airway diffusing capacity and the maximum flux of NO in the airways. Axial diffusion reduces exhaled NO concentrations because of diffusion of NO from the airways to the alveolar region of the lungs. The magnitude is inversely related to exhalation flow rate. To simulate experimental data from two different breathing maneuvers, NO airway diffusing capacity and maximum flux of NO in the airways needed to be increased approximately fourfold. These results depend strongly on the assumption of a significant production of NO in the small airways. We conclude that axial diffusion may decrease exhaled NO levels; however, more advanced knowledge of the longitudinal distribution of NO production and diffusion is needed to develop a complete understanding of the impact of axial diffusion.

Airway contribution to alveolar nitric oxide in healthy subjects and stable asthma patients

2008 ◽  
Vol 104 (4) ◽  
pp. 918-924 ◽  
Author(s):  
Yannick Kerckx ◽  
Alain Michils ◽  
Alain Van Muylem
Keyword(s):  
Nitric Oxide ◽  
Asthma Control ◽  
Healthy Subjects ◽  
Molecular Diffusion ◽  
Forced Expiratory Volume ◽  
No Production ◽  
Asthma Control Questionnaire ◽  
Asthma Patients ◽  
The Impact

Alveolar nitric oxide (NO) concentration (FaNO), increasingly considered in asthma, is currently interpreted as a reflection of NO production in the alveoli. Recent modeling studies showed that axial molecular diffusion brings NO molecules from the airways back into the alveolar compartment during exhalation (backdiffusion) and contributes to FaNO. Our objectives in this study were 1) to simulate the impact of backdiffusion on FaNO and to estimate the alveolar concentration actually due to in situ production (FaNO,prod); and 2) to determine actual alveolar production in stable asthma patients with a broad range of NO bronchial productions. A model incorporating convection and diffusion transport and NO sources was used to simulate FaNO and exhaled NO concentration at 50 ml/s expired flow (FeNO) for a range of alveolar and bronchial NO productions. FaNO and FeNO were measured in 10 healthy subjects (8 men; age 38 ± 14 yr) and in 21 asthma patients with stable asthma [16 men; age 33 ± 13 yr; forced expiratory volume during 1 s (FEV1) = 98.0 ± 11.9%predicted]. The Asthma Control Questionnaire (Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Chest 115: 1265–1270, 1999) assessed asthma control. Simulations predict that, because of backdiffusion, FaNO and FeNO are linearly related. Experimental results confirm this relationship. FaNO,prod may be derived by FaNO,prod = (FaNO − 0.08·FeNO)/0.92 ( Eq. 1 ). Based on Eq. 1 , FaNO,prod is similar in asthma patients and in healthy subjects. In conclusion, the backdiffusion mechanism is an important determinant of NO alveolar concentration. In stable and unobstructed asthma patients, even with increased bronchial NO production, alveolar production is normal when appropriately corrected for backdiffusion.

Basal and induced NO formation in the pharyngo-oral tract influences estimates of alveolar NO levels

2009 ◽  
Vol 106 (2) ◽  
pp. 513-519 ◽  
Author(s):  
Andrei Malinovschi ◽  
Christer Janson ◽  
Lena Holm ◽  
Lennart Nordvall ◽  
Kjell Alving
Keyword(s):  
Nitric Oxide ◽  
Healthy Subjects ◽  
Fold Increase ◽  
Peripheral Inflammation ◽  
Flow Rates ◽  
Axial Diffusion ◽  
Dietary Nitrate ◽  
No Formation ◽  
Nitrate Load ◽  
Nitrate And Nitrite

The present study analyzed how models currently used to distinguish alveolar from bronchial contribution to exhaled nitric oxide (NO) are affected by manipulation of NO formation in the pharyngo-oral tract. Exhaled NO was measured at multiple flow rates in 15 healthy subjects in two experiments: 1) measurements at baseline and 5 min after chlorhexidine (CHX) mouthwash and 2) measurements at baseline, 60 min after ingestion of 10 mg NaNO3/kg body wt, and 5 min after CHX mouthwash. Alveolar NO concentration (CalvNO) and bronchial flux (J′awNO) were calculated by using the slope-intercept model with or without adjustment for trumpet shape of airways and axial diffusion (TMAD). Salivary nitrate and nitrite were measured in the second experiment. CalvNO [median (range)] was reduced from 1.16 ppb (0.77, 1.96) at baseline to 0.84 ppb (0.57, 1.48) 5 min after CHX mouthwash ( P < 0.001). The TMAD-adjusted CalvNO value after CHX mouthwash was 0.50 ppb (0, 0.85). The nitrate load increased J′awNO from 32.2 nl/min (12.2, 60.3) to 57.1 nl/min (22.0, 119) in all subjects and CalvNO from 1.47 ppb (0.73, 1.95) to 1.87 ppb (10.85, 7.20) in subjects with high nitrate turnover (>10-fold increase of salivary nitrite after nitrate load). CHX mouthwash reduced CalvNO levels to 1.15 ppb (0.72, 2.07) in these subjects with high nitrate turnover. All these results remained consistent after TMAD adjustment. We conclude that estimated alveolar NO concentration is affected by pharyngo-oral tract production of NO in healthy subjects, with a decrease after CHX mouthwash. Moreover, unknown ingestion of dietary nitrate could significantly increase estimated alveolar NO in subjects with high nitrate turnover, and this might be falsely interpreted as a sign of peripheral inflammation. These findings were robust for TMAD.

Deferiprone increases endothelial nitric oxide synthase phosphorylation and nitric oxide production

2018 ◽  
Vol 96 (9) ◽  
pp. 879-885 ◽  
Author(s):  
Thanaporn Sriwantana ◽  
Pornpun Vivithanaporn ◽  
Kittiphong Paiboonsukwong ◽  
Krit Rattanawonsakul ◽  
Sirada Srihirun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Healthy Subjects ◽  
Iron Chelation ◽  
No Production ◽  
Hemoglobin E ◽  
Enos Phosphorylation

Iron chelation can improve endothelial function. However, effect on endothelial function of deferiprone has not been reported. We hypothesized deferiprone could promote nitric oxide (NO) production in endothelial cells. We studied effects of deferiprone on blood nitrite and blood pressure after single oral dose (25 mg/kg) in healthy subjects and hemoglobin E/β-thalassemia patients. Further, effects of deferiprone on NO production and endothelial NO synthase (eNOS) phosphorylation in primary human pulmonary artery endothelial cells (HPAEC) were investigated in vitro. Blood nitrite levels were higher in patients with deferiprone therapy than those without deferiprone (P = 0.023, n = 16 each). Deferiprone increased nitrite in plasma and whole blood of healthy subjects (P = 0.002 and 0.044) and thalassemia patients (P = 0.003 and 0.046) at time 180 min (n = 20 each). Asymptomatic reduction in diastolic blood pressure (P = 0.005) and increase in heart rate (P = 0.009) were observed in healthy subjects, but not in thalassemia patients. In HPAEC, deferiprone increased cellular nitrite and phospho-eNOS (Ser1177) (P = 0.012 and 0.035, n = 6) without alteration in total eNOS protein and mRNA. We conclude that deferiprone can induce NO production by enhancing eNOS phosphorylation in endothelial cells.

Exhaled nitric oxide after inhalation of isotonic and hypotonic solutions in healthy subjects

2001 ◽  
Vol 101 (6) ◽  
pp. 645-650 ◽  
Author(s):  
Mauro MANISCALCO ◽  
Alessandro VATRELLA ◽  
George CREMONA ◽  
Luigi CARRATÙ ◽  
Matteo SOFIA
Keyword(s):  
Nitric Oxide ◽  
Healthy Subjects ◽  
No Production ◽  
Mechanical Stimuli ◽  
Isotonic Solution ◽  
Double Blind ◽  
Baseline Values ◽  
Significant Change ◽  
Synthase Inhibitor ◽  
Airway Conductance

Airway nitric oxide (NO) homoeostasis is influenced by chemical and mechanical stimuli in humans; airway epithelium, which is an important site of NO production, is sensitive to osmotic challenge. The effect of inhaled hypotonic solutions on exhaled NO (eNO) is not known. In this study we evaluated the effect of ultrasonically nebulized distilled water (UNDW), a hypotonic indirect stimulus, on eNO levels. A total of 10 non-smoking healthy subjects were enrolled in the study. eNO was detected by chemiluminescence, and specific airway conductance (sGaw) was measured by plethysmography. Bronchial challenges with UNDW and with an isotonic solution were performed according to a double-blind experimental design. Baseline levels of eNO were 28.1±14.7p.p.b. UNDW did not cause any significant change in sGaw (from 0.190±0.029 to 0.181±0.036cmH2Oċs-1). With respect to baseline values, the eNO concentration decreased significantly after inhalation of 8 or 16ml of UNDW (from 26.0±13.1 to 17.2±8.5 and 16.6±7.7p.p.b. respectively; P < 0.001, n = 10). After bronchial challenge with UNDW, eNO was significantly reduced in comparison with after inhalation of the isotonic solution. In five subjects, pretreatment with NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor NO synthesis, decreased NO levels from 21.7±8.5 to 10.0±3.3p.p.b. Subsequent inhalation of 16ml of UNDW did not cause any further decrease in NO levels (10.1±3.7p.p.b.; not significant compared with l-NAME). We conclude that inhalation of aqueous solutions decreases eNO levels in healthy subjects, and that this effect is not associated with any significant change in airway calibre. The UNDW-induced decrease in eNO is not enhanced by pretreatment with the NO synthase inhibitor l-NAME, suggesting that inhaled solutions may interfere with the airway NO pathway in humans.

scholarly journals Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox

2004 ◽  
Vol 97 (3) ◽  
pp. 874-882 ◽  
Author(s):  
Hye-Won Shin ◽  
Peter Condorelli ◽  
Christine M. Rose-Gottron ◽  
Dan M. Cooper ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Flow Rate ◽  
Compartment Model ◽  
Breath Hold ◽  
Axial Diffusion ◽  
Molecular Diffusivity ◽  
Exhaled No ◽  
Two Compartment Model ◽  
Insufflating Gas ◽  
The Impact

Exhaled nitric oxide (NO) is a potential noninvasive index of lung inflammation and is thought to arise from the alveolar and airway regions of the lungs. A two-compartment model has been used to describe NO exchange; however, the model neglects axial diffusion of NO in the gas phase, and recent theoretical studies suggest that this may introduce significant error. We used heliox (80% helium, 20% oxygen) as the insufflating gas to probe the impact of axial diffusion (molecular diffusivity of NO is increased 2.3-fold relative to air) in healthy adults (21–38 yr old, n = 9). Heliox decreased the plateau concentration of exhaled NO by 45% (exhalation flow rate of 50 ml/s). In addition, the total mass of NO exhaled in phase I and II after a 20-s breath hold was reduced by 36%. A single-path trumpet model that considers axial diffusion predicts a 50% increase in the maximum airway flux of NO and a near-zero alveolar concentration (CaNO) and source. Furthermore, when NO elimination is plotted vs. constant exhalation flow rate (range 50–500 ml/s), the slope has been previously interpreted as a nonzero CaNO (range 1–5 ppb); however, the trumpet model predicts a positive slope of 0.4–2.1 ppb despite a zero CaNO because of a diminishing impact of axial diffusion as flow rate increases. We conclude that axial diffusion leads to a significant backdiffusion of NO from the airways to the alveolar region that significantly impacts the partitioning of airway and alveolar contributions to exhaled NO.

A different analysis applied to a mathematical model on output of exhaled nitric oxide

2005 ◽  
Vol 99 (1) ◽  
pp. 378-380 ◽  
Author(s):  
Bart L. Rottier ◽  
Judith Cohen ◽  
Thom W. van der Mark ◽  
W. Rob Douma ◽  
Eric J. Duiverman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Elimination Rate ◽  
Compartment Model ◽  
Phase Iii ◽  
Exhaled Breath ◽  
Dynamic Relationship ◽  
Exhaled No ◽  
Two Compartment Model ◽  
Conducting Airways ◽  
The Relationship

The following is the abstract of the article discussed in the following letter: The relatively recent detection of nitric oxide (NO) in the exhaled breath has prompted a great deal of experimentation in an effort to understand the pulmonary exchange dynamics. There has been very little progress in theoretical studies to assist in the interpretation of the experimental results. We have developed a two-compartment model of the lungs in an effort to explain several fundamental experimental observations. The model consists of a nonexpansile compartment representing the conducting airways and an expansile compartment representing the alveolar region of the lungs. Each compartment is surrounded by a layer of tissue that is capable of producing and consuming NO. Beyond the tissue barrier in each compartment is a layer of blood representing the bronchial circulation or the pulmonary circulation, which are both considered an infinite sink for NO. All parameters were estimated from data in the literature, including the production rates of NO in the tissue layers, which were estimated from experimental plots of the elimination rate of NO at end exhalation (ENO) vs. the exhalation flow rate (V̇e). The model is able to simulate the shape of the NO exhalation profile and to successfully simulate the following experimental features of endogenous NO exchange: 1) an inverse relationship between exhaled NO concentration and V̇E, 2) the dynamic relationship between the phase III slope and V̇E, and 3) the positive relationship between ENO and V̇E. The model predicts that these relationships can be explained by significant contributions of NO in the exhaled breath from the nonexpansile airways and the expansile alveoli. In addition, the model predicts that the relationship between ENO and V̇E can be used as an index of the relative contributions of the airways and the alveoli to exhaled NO.

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