Flow-independent nitric oxide exchange parameters in healthy adults.

Currently accepted techniques utilize the plateau concentration of nitric oxide (NO) at a constant exhalation flow rate to characterize NO exchange, which cannot sufficiently distinguish airway and alveolar sources. Using nonlinear least squares regression and a two-compartment model, we recently described a new technique (Tsoukias et al. J Appl Physiol 91: 477-487, 2001), which utilizes a preexpiratory breath hold followed by a decreasing flow rate maneuver, to estimate three flow-independent NO parameters: maximum flux of NO from the airways (J(NO,max), pl/s), diffusing capacity of NO in the airways (D(NO,air), pl x s(-1) x ppb(-1)), and steady-state alveolar concentration (C(alv,ss), ppb). In healthy adults (n = 10), the optimal breath-hold time was 20 s, and the mean (95% intramaneuver, intrasubject, and intrapopulation confidence interval) J(NO,max), D(NO,air), and C(alv,ss) are 640 (26, 20, and 15%) pl/s, 4.2 (168, 87, and 37%) pl x s(-1) x ppb(-1), and 2.5 (81, 59, and 21%) ppb, respectively. J(NO,max) can be estimated with the greatest certainty, and the variability of all the parameters within the population of healthy adults is significant. There is no correlation between the flow-independent NO parameters and forced vital capacity or the ratio of forced expiratory volume in 1 s to forced vital capacity. With the use of these parameters, the two-compartment model can accurately predict experimentally measured plateau NO concentrations at a constant flow rate. We conclude that this new technique is simple to perform and can simultaneously characterize airway and alveolar NO exchange in healthy adults with the use of a single breathing maneuver.     

Examining axial diffusion of nitric oxide in the lungs using heliox and breath hold.

Exhaled nitric oxide (NO) is highly dependent on exhalation flow; thus exchange dynamics of NO have been described by multicompartment models and a series of flow-independent parameters that describe airway and alveolar exchange. Because the flow-independent NO airway parameters characterize features of the airway tissue (e.g., wall concentration), they should also be independent of the physical properties of the insufflating gas. We measured the total mass of NO exhaled (A(I,II)) from the airways after five different breath-hold times (5-30 s) in healthy adults (21-38 yr, n = 9) using air and heliox as the insufflating gas, and then modeled A(I,II) as a function of breath-hold time to determine airway NO exchange parameters. Increasing breath-hold time results in an increase in A(I,II) for both air and heliox, but A(I,II) is reduced by a mean (SD) of 31% (SD 6) (P < 0.04) in the presence of heliox, independent of breath-hold time. However, mean (SD) values (air, heliox) for the airway wall diffusing capacity [3.70 (SD 4.18), 3.56 pl.s(-1).ppb(-1) (SD 3.20)], the airway wall concentration [1,439 (SD 487), 1,503 ppb (SD 644>)], and the maximum airway wall flux [4,156 (SD 2,502), 4,412 pl/s (SD 2,906)] using a single-path trumpet-shaped airway model that considers axial diffusion were independent of the insufflating gas (P > 0.55). We conclude that a single-path trumpet model that considers axial diffusion captures the essential features of airway wall NO exchange and confirm earlier reports that the airway wall concentration in healthy adults exceeds 1 ppm and thus approaches physiological concentrations capable of modulating smooth muscle tone.     

Impact of axial diffusion on nitric oxide exchange in the lungs.

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.     

Characterizing airway and alveolar nitric oxide exchange during tidal breathing using a three-compartment model.

Exhaled nitric oxide (NO) may be a useful marker of lung inflammation, but the concentration is highly dependent on exhalation flow rate due to a significant airway source. Current methods for partitioning pulmonary NO gas exchange into airway and alveolar regions utilize multiple exhalation flow rates or a single-breath maneuver with a preexpiratory breath hold, which is cumbersome for children and individuals with compromised lung function. Analysis of tidal breathing data has the potential to overcome these limitations, while still identifying region-specific parameters. In six healthy adults, we utilized a three-compartment model (two airway compartments and one alveolar compartment) to identify two potential flow-independent parameters that represent the average volumetric airway flux (pl/s) and the time-averaged alveolar concentration (parts/billion). Significant background noise and distortion of the signal from the sampling system were compensated for by using a Gaussian wavelet filter and a series of convolution integrals. Mean values for average volumetric airway flux and time-averaged alveolar concentration were 2,500 +/- 2,700 pl/s and 3.2 +/- 3.4 parts/billion, respectively, and were strongly correlated with analogous parameters determined from vital capacity breathing maneuvers. Analysis of multiple tidal breaths significantly reduced the standard error of the parameter estimates relative to the single-breath technique. Our initial assessment demonstrates the potential of utilizing tidal breathing for noninvasive characterization of pulmonary NO exchange dynamics.     

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.     

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

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 (Ca(NO)) 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 Ca(NO) (range 1-5 ppb); however, the trumpet model predicts a positive slope of 0.4-2.1 ppb despite a zero Ca(NO) 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.     

Modeling pulmonary nitric oxide exchange.

Nitric oxide (NO) was first detected in the exhaled breath more than a decade ago and has since been investigated as a noninvasive means of assessing lung inflammation. Exhaled NO arises from the airway and alveolar compartments, and new analytical methods have been developed to characterize these sources. A simple two-compartment model can adequately represent many of the observed experimental observations of exhaled concentration, including the marked dependence on exhalation flow rate. The model characterizes NO exchange by using three flow-independent exchange parameters. Two of the parameters describe the airway compartment (airway NO diffusing capacity and either the maximum airway wall NO flux or the airway wall NO concentration), and the third parameter describes the alveolar region (steady-state alveolar NO concentration). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs. Several analytical techniques have been developed to estimate the flow-independent parameters in both health and disease. Future studies will focus on improving our fundamental understanding of NO exchange dynamics, the analytical techniques used to characterize NO exchange dynamics, as well as the physiological interpretation and the clinical relevance of the flow-independent parameters.     

Assessment of exhaled nitric oxide kinetics in healthy infants.

Exhaled nitric oxide (Fe(NO)) measurements provide a noninvasive approach to the evaluation of airway inflammation. Flow-independent NO exchange parameters [airway NO transfer factor (D(NO)) and airway wall NO concentration (Cw(NO))] can be estimated from Fe(NO) measurements at low flows and may elucidate mechanisms of disturbances in NO exchange. We measured Fe(NO) in sedated infants by using an adaptation of a raised lung volume rapid thoracic compression technique that creates forced expiration through a mass-flow controller that lasts 5-10 s, at a constant preset flow. We measured Fe(NO) at expired flows of 50, 25, and 15 ml/s in five healthy infants (7-31 mo). Median Fe(NO) increased [24, 40, and 60 parts per billion (ppb)] with decreasing expiratory flows (50, 25, and 15 ml/s). Group median (range) for D(NO) and Cw(NO) were 12.7 (3.2-37) x 10(-3) nl. s(-1). ppb(-1) and 108.9 (49-385) ppb, respectively, similar to values reported in healthy adults. Exhaled NO is flow dependent; flow-independent parameters of exhaled NO kinetics can be assessed in infants and are similar to values described in adults.     

A new and more accurate technique to characterize airway nitric oxide using different breath-hold times.

Exhaled nitric oxide (NO) arises from both airway and alveolar regions of the lungs, which provides an opportunity to characterize region-specific inflammation. Current methodologies rely on vital capacity breathing maneuvers and controlled exhalation flow rates, which can be difficult to perform, especially for young children and individuals with compromised lung function. In addition, recent theoretical and experimental studies demonstrate that gas-phase axial diffusion of NO has a significant impact on the exhaled NO signal. We have developed a new technique to characterize airway NO, which requires a series of progressively increasing breath-hold times followed by exhalation of only the airway compartment. Using our new technique, we determined values (means +/- SE) in healthy adults (20-38 yr, n = 8) for the airway diffusing capacity [4.5 +/- 1.6 pl.s(-1).parts per billion (ppb)(-1)], the airway wall concentration (1,340 +/- 213 ppb), and the maximum airway wall flux (4,350 +/- 811 pl/s). The new technique is simple to perform, and application of this data to simpler models with cylindrical airways and no axial diffusion yields parameters consistent with previous methods. Inclusion of axial diffusion as well as an anatomically correct trumpet-shaped airway geometry results in significant loss of NO from the airways to the alveolar region, profoundly impacting airway NO characterization. In particular, the airway wall concentration is more than an order of magnitude larger than previous estimates in healthy adults and may approach concentrations (approximately 5 nM) that can influence physiological processes such as smooth muscle tone in disease states such as asthma.     

Single-exhalation profiles of NO and CO2 in humans: effect of dynamically changing flow rate

Endogenousproduction of nitric oxide (NO) in the human lungs has many importantpathophysiological roles and can be detected in the exhaled breath. Anunderstanding of the factors that dictate the shape of the NOexhalation profile is fundamental to our understanding of normal anddiseased lung function. We collected single-exhalation profiles of NOand CO₂ from normal human subjectsafter inhalation of ambient air (~15 parts/billion) and examined theeffect of a 15-s breath hold and exhalation flow rate(_E) on thefollowing features of the NO profile:1) series dead space,2) average concentration in phaseIII with respect to time and volume,3) normalized slope of phase IIIwith respect to time and volume, and4) elimination rate at endexhalation. The dead space is ~50% smaller for NO than forCO₂ and is substantially reducedafter a breath hold. The concentration of exhaled NO is inverselyrelated to _E,but the average NO concentration with respect to time has a stronger inverse relationship than that with respect to volume. The normalized slope of phase III NO with respect to time and that with respect tovolume are negative at a constant_E but can bemade to change signs if the flow rate continuously decreases during theexhalation. In addition, NO elimination at end exhalation vs._E produces anonzero intercept and slope that are subject dependent and can be usedto quantitate the relative contribution of the airways and the alveolito exhaled NO. We conclude that exhaled NO has an airway and analveolar source.

     

Indirect assessment of mucosal surface temperatures in the airways: theory and tests

We developed and tested a method, based on conduction heat transfer analysis, to infer airway mucosal temperatures from airstream temperature-time profiles during breath-hold maneuvers. The method assumes that radial conduction of heat from the mucosal wall to inspired air dominates heat exchange during a breath-hold maneuver and uses a simplified conservation of energy analysis to extrapolate wall temperatures from air temperature vs. time profiles. Validation studies were performed by simultaneously measuring air and wall temperatures by use of a retractable basket probe in the upper airways of human volunteers and intrathoracic airways of paralyzed intubated dogs during breath holding. In both protocols, a good correlation was demonstrated between directly measured wall temperatures and those calculated from adjacent airstream temperature vs. time profiles during a breath hold. We then calculated intrathoracic bronchial wall temperatures from breath-hold airstream temperature-time profiles recorded in normal human subjects after cold air hyperpnea at 30 and 80 l/min. The calculations show airway wall temperatures in the upper intrathoracic airways that are below core body temperature during hyperpnea of frigid air and upper thoracic airways that are cooler than more peripheral airways. The data suggest that the magnitude of local intrathoracic heat/water flux is not represented by heat/water loss measurements at the airway opening. Both the magnitude and locus of heat transport during cold gas hyperventilation vary with changes in inspired gas temperature and minute ventilation; both may be important determinants of airway responses.     

Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge.

Exhaled nitric oxide (NO) levels are high in asthmatic subjects and increase with exacerbations. We hypothesized that higher levels of NO observed during asthma exacerbations are due to increased synthesis of NO. Exhaled NO and peak flows were measured in 11 asthmatic and 9 healthy control subjects before and after experimental asthmatic response induced by whole lung allergen challenge. Baseline peak flows of asthmatics were significantly lower than controls and decreased significantly immediately after challenge (P = 0.004). NO was measured by collecting exhaled breaths without breath hold (NO0) and after a 15-s breath hold (NO15). The rate of NO accumulation over time [parts/billion per second (ppb/s)] was calculated by DeltaNO/Deltat = (NO15 - NO0)/15, where Delta denotes a change and t is time. The NO accumulation rates in asthmatic and control subjects were similar at baseline; however, NO accumulation at 24 h increased threefold from baseline in asthmatic compared with control subjects (asthmatic subjects, 0.6 +/- 0.2 ppb/s; control subjects, 0.2 +/- 0.1 ppb/s; P = 0.01). Our study suggests that increased NO during an asthma exacerbation is due to increased synthesis, perhaps by increased expression of NO synthases.     

Exhaled NO is reduced at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets

Altered nitric oxide (NO) production could contribute to the pathogenesis of hypoxia-induced pulmonary hypertension. To determine whether parameters of lung NO are altered at an early stage of hypoxia-induced pulmonary hypertension, newborn piglets were exposed to room air (control, n = 21) or 10% O(2) (hypoxia, n = 19) for 3-4 days. Some lungs were isolated and perfused for measurement of exhaled NO output and the perfusate accumulation of nitrite and nitrate (NOx-), the stable metabolites of NO. Pulmonary arteries (20-600-microm diameter) and their accompanying airways were dissected from other lungs and incubated for NOx- determination. Abundances of the nitric oxide synthase (NOS) isoforms endothelial NOS and neural NOS were assessed in homogenates of PAs and airways. The perfusate NOx- accumulation was similar, whereas exhaled NO output was lower for isolated lungs of hypoxic, compared with control, piglets. The incubation solution NOx- did not differ between pulmonary arteries (PAs) of the two groups but was lower for airways of hypoxic, compared with control, piglets. Abundances of both eNOS and nNOS proteins were similar for PA homogenates from the two groups of piglets but were increased in airway homogenates of hypoxic compared with controls. The NO pathway is altered in airways, but not in PAs, at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets.     

Microscopic modeling of NO and S-nitrosoglutathione kinetics and transport in human airways.

Nitric oxide (NO) appears in the exhaled breath and is elevated in inflammatory diseases. We developed a steady-state mathematical model of the bronchial mucosa for normal small and large airways to understand NO and S-nitrosoglutathione (GSNO) kinetics and transport using data from the existing literature. Our model predicts that mean steady-state NO and GSNO concentrations for large airways (generation 1) are 2.68 nM and 113 pM, respectively, in the epithelial cells and 0.11 nM (approximately 66 ppb) and 507 nM in the mucus. For small airways (generation 15), the mean concentrations of NO and GSNO, respectively, are 0.26 nM and 21 pM in the epithelial cells and 0.02 nM (approximately 12 ppb) and 132 nM in the mucus. The concentrations in the mucus compare favorably to experimentally measured values. We conclude that 1) the majority of free NO in the mucus, and thus exhaled NO, is due to diffusion of free NO from the epithelial cell and 2) the heterogeneous airway contribution to exhaled NO is due to heterogeneous airway geometries, such as epithelium and mucus thickness.     

Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans.

Human airways produce nitric oxide (NO), and exhaled NO increases as expiratory flow rates fall. We show that mixing during exhalation between the NO produced by the lower, alveolar airways (VL(NO)) and the upper conducting airways (VU(NO)) explains this phenomenon and permits measurement of VL(NO), VU(NO), and the NO diffusing capacity of the conducting airways (DU(NO)). After breath holding for 10-15 s the partial pressure of alveolar NO (PA) becomes constant, and during a subsequent exhalation at a constant expiratory flow rate the alveoli will deliver a stable amount of NO to the conducting airways. The conducting airways secrete NO into the lumen (VU(NO)), which mixes with PA during exhalation, resulting in the observed expiratory concentration of NO (PE). At fast exhalations, PA makes a large contribution to PE, and, at slow exhalations, NO from the conducting airways predominates. Simple equations describing this mixing, combined with measurements of PE at several different expiratory flow rates, permit calculation of PA, VU(NO), and DU(NO). VL(NO) is the product of PA and the alveolar airway diffusion capacity for NO. In seven normal subjects, PA = 1.6 +/- 0.7 x 10(-6) (SD) Torr, VL(NO) = 0.19 +/- 0.07 microl/min, VU(NO) = 0.08 +/- 0.05 microl/min, and DU(NO) = 0.4 +/- 0.4 ml. min(-1). Torr(-1). These quantitative measurements of VL(NO) and VU(NO) are suitable for exploring alterations in NO production at these sites by diseases and physiological stresses.     

Nitric oxide in the breath of bottlenose dolphins: Effects of breath hold duration,feeding, and lung disease

Breath analysis, including measurement of nitric oxide (NO), is a noninvasive diagnostic tool that may help evaluate cetacean health. This is the first report on the effects of breath hold duration, feeding, and lung disease on NO in dolphin exhaled breath. Three healthy dolphins were trained to hold their breath for 30, 60, 90, and 120 s and then exhale into an underwater funnel. Exhaled NO values from 157 breath samples were compared among three healthy dolphins by breath hold time and after fasting and feeding. Exhaled NO values were also measured in two dolphins with pulmonary disease. NO in dolphin breath was higher compared to ambient air; healthy dolphins had higher NO concentrations in their breath after feeding compared to after overnight fasting; and there were no significant differences in exhaled NO levels by breath hold duration. A dolphin with Mycoplasma‐associated pneumonia and chronic gastrointestinal disease had higher postprandial exhaled NO levels compared to healthy controls. This study demonstrates, contrary to previous publications, that dolphins exhale NO. Given the high standard deviations present in exhaled breath NO values, future studies are needed to further standardize collection methods or identify more reliable samples (e.g., blood).     

Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.

This study tested the effects of inhaled nitric oxide [NO; 20 parts per million (ppm)] during normoxic and hypoxic (fraction of inspired O(2) = 14%) exercise on gas exchange in athletes with exercise-induced hypoxemia. Trained male cyclists (n = 7) performed two cycle tests to exhaustion to determine maximal O(2) consumption (VO(2 max)) and arterial oxyhemoglobin saturation (Sa(O(2)), Ohmeda Biox ear oximeter) under normoxic (VO(2 max) = 4.88 +/- 0.43 l/min and Sa(O(2)) = 90.2 +/- 0.9, means +/- SD) and hypoxic (VO(2 max) = 4.24 +/- 0.49 l/min and Sa(O(2)) = 75.5 +/- 4.5) conditions. On a third occasion, subjects performed four 5-min cycle tests, each separated by 1 h at their respective VO(2 max), under randomly assigned conditions: normoxia (N), normoxia + NO (N/NO), hypoxia (H), and hypoxia + NO (H/NO). Gas exchange, heart rate, and metabolic parameters were determined during each condition. Arterial blood was drawn at rest and at each minute of the 5-min test. Arterial PO(2) (Pa(O(2))), arterial PCO(2), and Sa(O(2)) were determined, and the alveolar-arterial difference for PO(2) (A-aDO(2)) was calculated. Measurements of Pa(O(2)) and Sa(O(2)) were significantly lower and A-aDO(2) was widened during exercise compared with rest for all conditions (P < 0.05). No significant differences were detected between N and N/NO or between H and H/NO for Pa(O(2)), Sa(O(2)) and A-aDO(2) (P > 0.05). We conclude that inhalation of 20 ppm NO during normoxic and hypoxic exercise has no effect on gas exchange in highly trained cyclists.     

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.     

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

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'aw(NO) = 770 +/- 470 compared with 440 +/- 270 pl/s), whereas estimates for the steady-state alveolar concentration are statistically lower (CA(NO) = 0.66 +/- 0.98 compared with 1.2 +/- 0.80 parts/billion). Furthermore, CA(NO) 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.     

The effect of temperature on C(4)-type leaf photosynthesis parameters

C(4)-type photosynthesis is known to vary with growth and measurement temperatures. In an attempt to quantify its variability with measurement temperature, the photosynthetic parameters - the maximum catalytic rate of the enzyme ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco) (V(cmax)), the maximum catalytic rate of the enzyme phosphoenolpyruvate carboxylase (PEPC) (V(pmax)) and the maximum electron transport rate (J(max)) - were examined. Maize plants were grown in climatic-controlled phytotrons, and the curves of net photosynthesis (A(n)) versus intercellular air space CO(2) concentrations (C(i)), and A(n) versus photosynthetic photon flux density (PPFD) were determined over a temperature range of 15-40 degrees C. Values of V(cmax), V(pmax) and J(max) were computed by inversion of the von Caemmerer & Furbank photosynthesis model. Values of V(pmax) and J(max) obtained at 25 degrees C conform to values found in the literature. Parameters for an Arrhenius equation that best fits the calculated values of V(cmax), V(pmax) and J(max) are then proposed. These parameters should be further tested with C(4) plants for validation. Other model key parameters such as the mesophyll cell conductance to CO(2) (g(i)), the bundle sheath cells conductance to CO(2) (g(bs)) and Michaelis-Menten constants for CO(2) and O(2) (K(c), K(p) and K(o)) also vary with temperature and should be better parameterized.