Exhaled nitric oxide in pulmonary diseases: a comprehensive review.

Purpose of reviewThe purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism.Recent findingsThe role of the cofactor tetrahydrobiopterin in nitric oxide production and

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Regulation of nitric oxide production in health and disease

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.

Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.

Nitric oxide in adaptation to altitude

The aim of the present study was to calculate reference equations for carbon monoxide and nitric oxide transfer, measured in two distinct populations. The transfer factor of the lung for nitric oxide (TL,NO) and carbon monoxide (TL,CO) were measured in 303 people aged 18-94 yrs. Measurements were similarly made in two distant cities, using the single-breath technique. Capillary lung volume (Vc) and membrane conductance, the diffusing capacity of the membrane (Dm), for carbon monoxide (Dm,co) were derived. The transfer of both gases appeared to depend upon age, height, sex and localisation. The rate of decrease in both transfers increased after the age of 59 yrs. TL,No/alveolar volume (VA) and TL,CO/VA were only age-dependent. The mean TL,No/TL,co was 4.75 and the mean Dm/Vc was 6.17 min -1 kPa -1 ; these parameters were independent of any covariate. Vc and Dm,co calculations depend upon the choice of coefficients included in the Roughton-Forster equation. Values of 1.97 for Dm,NO/Dm,co ratio and 12.86 min kPa -1 for 1/red cell CO conductance are recommended. The scatter of transfer reference values in the literature, including the current study, is wide. The present results suggest that differences might be due to the populations themselves and not the methods alone.

European reference equations for CO and NO lung transfer. Commentary

Elevated exhaled nitric oxide (NO) in the breath of asthmatic subjects is thought to be a noninvasive marker of lung inflammation. Asthma is also characterized by heterogeneous bronchoconstriction and inflammation, which impact the spatial distribution of ventilation in the lungs. Since exhaled NO arises from both airway and alveolar regions, and its level in exhaled breath depends strongly on flow, spatial heterogeneity in flow patterns and NO production may significantly affect the exhaled NO signal. To investigate the effect of these factors on exhaled NO profiles, we developed a multicompartment mathematical model of NO exchange using a trumpet-shaped central airway segment that bifurcates into two similarly shaped peripheral airway segments, each of which empties into an alveolar compartment. Heterogeneity in flow alone has only a minimal impact on the exhaled NO profile. In contrast, placing 70% of the total airway NO production in the central compartment or the distal poorly ventilated compartment can significantly increase (35%) or decrease (-10%) the plateau concentration, respectively. Reduced ventilation of the peripheral and acinar regions of the lungs with concomitant elevated NO production delays the rise of NO during exhalation, resulting in a positive phase III slope and reduced plateau concentration (-11%). These features compare favorably with experimentally observed profiles in exercise-induced asthma and cannot be simulated with single-path models. We conclude that variability in ventilation and NO production in asthmatic subjects impacts the shape of the exhaled NO profile and thus impacts the physiological interpretation.

Effect of heterogeneous ventilation and nitric oxide production on exhaled nitric oxide profiles

Exhaled nitric oxide (NO) is elevated in asthma, but the underlying mechanisms remain poorly understood. Recent results in subjects with asthma have reported a decrease in exhaled breath pH and amm...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.01012.2006

Airway nitric oxide release is reduced after PBS inhalation in asthma

Impulse noise injury prediction based on the cochlear energy.

Nitric oxide (NO) is detectable in exhaled breath and is thought to be a marker of lung inflammation. The multicompartment model of NO exchange in the lungs, which was previously introduced by our laboratory, considers parallel and serial heterogeneity in the proximal and distal regions and can simulate dynamic features of the NO exhalation profile, such as a sloping phase III region. Here, we present a detailed sensitivity analysis of the multicompartment model and then apply the model to a population of children with mild asthma. Latin hypercube sampling demonstrated that ventilation and structural parameters were not significant relative to NO production terms in determining the NO profile, thus reducing the number of free parameters from nine to five. Analysis of exhaled NO profiles at three flows (50, 100, and 200 ml/s) from 20 children (age 7–17 yr) with mild asthma representing a wide range of exhaled NO (4.9 ppb < fractional exhaled NO at 50 ml/s < 120 ppb) demonstrated that 90% of the children had a negative phase III slope. The multicompartment model could simulate the negative phase III slope by increasing the large airway NO flux and/or distal airway/alveolar concentration in the well-ventilated regions. In all subjects, the multicompartment model analysis improved the least-squares fit to the data relative to a single-path two-compartment model. We conclude that features of the NO exhalation profile that are commonly observed in mild asthma are more accurately simulated with the multicompartment model than with the two-compartment model. The negative phase III slope may be due to increased NO production in well-ventilated regions of the lungs.

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00795.2009

David A. Shelley

Papers

Effect of heterogeneous ventilation and nitric oxide production on exhaled nitric oxide profiles

Airway nitric oxide release is reduced after PBS inhalation in asthma

Impulse noise injury prediction based on the cochlear energy.

Quantifying proximal and distal sources of NO in asthma using a multicompartment model

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