Acinar effect of inhaled steroids evidenced by exhaled nitric oxide.

BACKGROUND: The effects of inhaled corticosteroids (ICSs) on distal lung inflammation, as assessed by alveolar nitric oxide concentration (C(A)NO), are a matter of debate. Recently, a theoretic study suggested that acinar airway obstruction that is relieved by ICS treatment and associated with a decrease in fraction of exhaled nitric oxide (FeNO) concentration might, paradoxically, increase C(A)NO. This increase could be a hallmark effect of ICSs at the acinar level. OBJECTIVE: In the light of this new hypothesis, we studied changes in C(A)NO and FeNO after administration of ICSs. METHODS: C(A)NO and FeNO were measured before and after ICS treatment of 38 steroid-naive patients with uncontrolled asthma who showed clinical improvement after ICS therapy. RESULTS: The average FeNO decreased from 78.3 to 28.9 ppb (P < .001); C(A)NO decreased from 7.7 to 4.3 ppb (P = .009). In 14 subjects (low-slope group), slope (= ΔC(A)NO/ΔFeNO) values (Δ = post-ICS - pre-ICS value) were less than the 95% normal CI (average ΔFeNO = -32.7 ppb and average ΔC(A)NO= +2.9 ppb). In this group, baseline C(A)NO was abnormally low when FeNO was taken into account. In 11 subjects (the high-slope group), the slope was above the normal interval (average ΔFeNO = -42.5 ppb and average ΔC(A)NO = -14.7 ppb). CONCLUSION: Opposite patterns (one that was predicted) can indicate peripheral actions of ICSs; this difference might account for conflicting data reported from studies using C(A)NO to determine the peripheral action of ICSs. We show that a low C(A)NO does not preclude distal inflammation.

Axial distribution heterogeneity of nitric oxide airway production in healthy adults.

Model simulations of nitric oxide (NO) transport considering molecular diffusion showed that the total bronchial NO production needed to reproduce a given exhaled value is deeply influenced by its axial distribution. Experimental data obtained by fibroscopy were available about proximal airway contribution (Silkoff PE, McClean PA, Caramori M, Slutsky AS. Zamel N. Respir Physiol 113: 33-38, 1998), and recent experiments using heliox instead of air gave insight on the peripheral airway production (Shin HW, Condorelli P, Rose-Gottron CM, Cooper DM, George SC. J Appl Physiol 97: 874-882, 2004; Kerckx Y, Michils A, Van Muylem A. J Appl Physiol 104: 918-924, 2008). This theoretical work aimed at obtaining a realistic distribution of NO production in healthy adults by meeting both proximal and peripheral experimental constraints. To achieve this, a model considering axial diffusion with geometrical boundaries derived from Weibel's morphometrical data was divided into serial compartments, each characterized by its axial boundaries and its part of bronchial NO production. A four-compartment model was able to meet both criteria. Two compartments were found to share all the NO production: one proximal (generations 0 and 1; 15-25% of the NO production) and one inside the acinus (proximal limit, generations 14-16; distal limit, generations 16 and 17; 75-85% of the NO production). Remarkably, this finding implies a quasi nil production in the main part of the conducting airways and in the acinar airways distal to generation 17. Given the chosen experimental outcomes and reliant on their accuracy, this very inhomogeneous distribution is likely the more realistic one that may be achieved with a "one-trumpet"-shaped model. Refinement should come from a more realistic description of the acinus structure.

The effect of posture-induced changes in peripheral nitric oxide uptake on exhaled nitric oxide.

Airway and alveolar NO contributions to exhaled NO are being extracted from exhaled NO measurements performed at different flow rates. To test the robustness of this method and the validity of the underlying model, we deliberately induced a change in NO uptake in the peripheral lung compartment by changing body posture between supine and prone. In 10 normal subjects, we measured exhaled NO at target flows ranging from 50 to 350 ml/s in supine and prone postures. Using two common methods, bronchial NO production [Jaw(NO)] and alveolar NO concentration (FANO) were extracted from exhaled NO concentration vs. flow or flow(-1) curves. There was no significant Jaw(NO) difference between prone and supine but a significant FANO decrease from prone to supine ranging from 23 to 33% depending on the method used. Total lung capacity was 7% smaller supine than prone (P = 0.03). Besides this purely volumetric effect, which would tend to increase FANO from prone to supine, the observed degree of FANO decrease from prone to supine suggests a greater opposing effect that could be explained by the increased lung capillary blood volume (V(c)) supine vs. prone (P = 0.002) observed in another set of 11 normal subjects. Taken together with the relative changes of NO and CO transfer factors, this V(c) change can be attributed mainly to pulmonary capillary recruitment from prone to supine. Realistic models for exhaled NO simulation should include the possibility that a portion of the pulmonary capillary bed is unavailable for NO uptake, with a maximum capacity of the pulmonary capillary bed in the supine posture.

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

Alveolar nitric oxide (NO) concentration (Fa(NO)), 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 Fa(NO). Our objectives in this study were 1) to simulate the impact of backdiffusion on Fa(NO) and to estimate the alveolar concentration actually due to in situ production (Fa(NO,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 Fa(NO) and exhaled NO concentration at 50 ml/s expired flow (Fe(NO)) for a range of alveolar and bronchial NO productions. Fa(NO) and Fe(NO) 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 (FEV(1)) = 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, Fa(NO) and Fe(NO) are linearly related. Experimental results confirm this relationship. Fa(NO,prod) may be derived by Fa(NO,prod) = (Fa(NO) - 0.08.Fe(NO))/0.92 (Eq. 1). Based on Eq. 1, Fa(NO,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.

Effect of airways constriction on exhaled nitric oxide.

While airway constriction has been shown to affect exhaled nitric oxide (NO), the mechanisms and location of constricted airways most likely to affect exhaled NO remain obscure. We studied the effects of histamine-induced airway constriction and ventilation heterogeneity on exhaled NO at 50 ml/s (Fe(NO,50)) and combined this with model simulations of Fe(NO,50) changes due to constriction of airways at various depths of the lung model. In 20 normal subjects, histamine induced a 26 +/- 15(SD)% Fe(NO,50) decrease, a 9 +/- 6% forced expiratory volume in 1 s (FEV(1)) decrease, a 19 +/- 9% mean forced midexpiratory flow between 25% and 75% forced vital capacity (FEF(25-75)) decrease, and a 94 +/- 119% increase in conductive ventilation heterogeneity. There was a significant correlation of Fe(NO,50) decrease with FEF(25-75) decrease (P = 0.006) but not with FEV(1) decrease or with increased ventilation heterogeneity. Simulations confirmed the negligible effect of ventilation heterogeneity on Fe(NO,50) and showed that the histamine-induced Fe(NO,50) decrease was due to constriction, with associated reduction in NO flux, of airways located proximal to generation 15. The model also indicated that the most marked effect of airways constriction on Fe(NO,50) is situated in generations 10-15 and that airway constriction beyond generation 15 markedly increases Fe(NO,50) due to interference with the NO backdiffusion effect. These mechanical factors should be considered when interpreting exhaled NO in lung disease.

Axial distribution of nitric oxide airway production in asthma patients.

In healthy subjects, axial distribution of nitric oxide (NO) airway production is likely heterogeneous: notably a distal peak of production in terminal bronchioles and a quasi-nil NO production in the most of the conducting airways. In asthma, few information exists about the contributions of the proximal and distal airways to NO overproduction. In 18 asthma patients, sites of constriction after methacholine and adenosine 5'-monophosphate (AMP) challenges were assessed by ventilation distribution tests with He and SF(6). The resulting decreases in fractional exhaled NO (FENO) were measured. Changes in He and SF(6) slopes indicated a pre-acinar bronchoconstriction due to AMP and a more proximal action for methacholine. FENO decreased by 38.7% and 20.2% (p<0.001) after AMP and methacholine challenges, respectively. Significant FENO decreases after AMP and methacholine implies substantial pre-acinar but also, contrary to healthy subjects, more proximal airway production. In conclusion, nitric oxide overproduction in asthma patients appears to involve the most part of the conducting airways.

Lung diffusing capacity for nitric oxide at lowered and raised ambient pressures.

Lung diffusing capacity for NO (DLNO) was determined in eight subjects at ambient pressures of 505, 1015, and 4053hPa (379, 761 and 3040mmHg) as they breathed normoxic gases. Mean values were 116.9±11.1 (SEM), 113.4±11.1 and 99.3±10.1mlmin(-1)hPa(-1)at 505, 1015, and 4053hPa, with a 13% difference between the two higher pressures (P=0.017). The data were applied to a model with two serially coupled conductances; the gas phase (DgNO, variable with pressure), and the alveolo-capillary membrane (DmNO, constant). The data fitted the model well and we conclude that diffusive transport of NO in the peripheral lung is inversely related to gas density. At normal pressure DmNO was approximately 5% larger than DLNO, suggesting that the Dg factor then is not negligible. We also conclude that the density of the breathing gas is likely to impact the backdiffusion of naturally formed NO from conducting airways to the alveoli.

Effects of ambient pressure on pulmonary nitric oxide.

Airway nitric oxide (NO) has been proposed to play a role in the development of high-altitude pulmonary edema. We undertook a study of the effects of acute changes of ambient pressure on exhaled and alveolar NO in the range 0.5-4 atmospheres absolute (ATA, 379-3,040 mmHg) in eight healthy subjects breathing normoxic nitrogen-oxygen mixtures. On the basis of previous work with inhalation of low-density helium-oxygen gas, we expected facilitated backdiffusion and lowered exhaled NO at 0.5 ATA and the opposite at 4 ATA. Instead, the exhaled NO partial pressure (Pe(NO)) did not differ between pressures and averaged 1.21 ± 0.16 (SE) mPa across pressures. As a consequence, exhaled NO fractions varied inversely with pressure. Alveolar estimates of the NO partial pressure differed between pressures and averaged 88 (P = 0.04) and 176 (P = 0.009) percent of control (1 ATA) at 0.5 and 4 ATA, respectively. The airway contribution to exhaled NO was reduced to 79% of control (P = 0.009) at 4 ATA. Our finding of the same Pe(NO) at 0.5 and 1 ATA is at variance with previous findings of a reduced Pe(NO) with inhalation of low-density gas at normal pressure, and this discrepancy may be due to the much longer durations of low-density gas breathing in the present study compared with previous studies with helium-oxygen breathing. The present data are compatible with the notion of an enhanced convective backtransport of NO, compensating for attenuated backdiffusion of NO with increasing pressure. An alternative interpretation is a pressure-induced suppression of NO formation in the airways.

Effect of blood redistribution on exhaled and alveolar nitric oxide: a hypergravity model study.

Alveolar (CA(NO)) and exhaled nitric oxide (FE(NO)) concentrations, mainly regarded as inflammation surrogates, may also be affected by perfusion redistribution changing alveolar transfer factor (DA(NO)). A model of blood redistribution is hypergravity, Karlsson et al. (2009b) found, at 2G, increases of 22% and 70%, for FE(NO), and CA(NO), respectively. The present study aimed at theoretically estimating the amplitude of DA(NO) changes that mimic these experimental data. An equation describing convection, diffusion and NO sources was solved in a 2-trumpet model (parallel dependent and non-dependent lung units). Acinar airways lumen reduction was also simulated. A reduction of 33% of the overall DA(NO) (-51% in the non-dependent unit) along with a 36% reduction of acinar airways lumen reproduced experimental findings. In conclusion, substantial FE(NO) and CA(NO) increases may be accounted for by a decrease of the alveolo-capillaries contact surface, here hypergravity-induced. Acinar airway constriction may also have a part in the overall FE(NO) increase.

Microgravity decreases and hypergravity increases exhaled nitric oxide.

Inhalation of toxic dust during planetary space missions may cause airway inflammation, which can be monitored with exhaled nitric oxide (NO). Gravity will differ from earth, and we hypothesized that gravity changes would influence exhaled NO by altering lung diffusing capacity and alveolar uptake of NO. Five subjects were studied during microgravity aboard the International Space Station, and 10 subjects were studied during hypergravity in a human centrifuge. Exhaled NO concentrations were measured during flows of 50 (all gravity conditions), 100, 200, and 500 ml/s (hypergravity). During microgravity, exhaled NO fell from a ground control value of 12.3 +/- 4.7 parts/billion (mean +/- SD) to 6.6 +/- 4.4 parts/billion (P = 0.016). In the centrifuge experiments and at the same flow, exhaled NO values were 16.0 +/- 4.3, 19.5 +/- 5.1, and 18.6 +/- 4.7 parts/billion at one, two, and three times normal gravity, where exhaled NO in hypergravity was significantly elevated compared with normal gravity (P