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.
George SC. Airway nitric oxide release is reduced after PBS inhalation in asthma. J Appl Physiol 102: 1028 -1033, 2007. First published November 16, 2006 doi:10.1152/japplphysiol.01012.2006.-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 ammonia, as well as altered expression and activity of glutaminase in both alveolar and airway epithelial cells. This suggests that pH-dependent nitrite conversion to NO may be a source of exhaled NO in the asthmatic airway epithelium. However, the anatomic location (i.e., airway or alveolar region) of this pH-dependent NO release has not been investigated and could impact potential therapeutic strategies. We quantified airway (proximal) and alveolar (peripheral) contributions to exhaled NO at baseline and then after PBS inhalation in stable (mild-intermittent to severe) asthmatic subjects (20 -44 yr old; n ϭ 9) and healthy controls (22-41 yr old; n ϭ 6). The mean (SD) maximum airway wall flux (pl/s) and alveolar concentration (ppb) at baseline in asthma subjects and healthy controls was 2,530 (2,572) and 5.42 (7.31) and 1,703 (1,567) and 1.88 (1.29), respectively. Compared with baseline, there is a significant decrease in the airway wall flux of NO in asthma as early as 15 min and continuing for up to 60 min (maximum Ϫ28% at 45 min) after PBS inhalation without alteration of alveolar concentration. Healthy control subjects did not display any changes in exhaled NO. We conclude that elevated airway NO at baseline in asthma is reduced by inhaled PBS. Thus airway NO may be, in part, due to nitrite conversion to NO and is consistent with airway pH dysregulation in asthma.pH; inflammation NITRIC OXIDE (NO) appears in the exhaled breath (1, 9) and has been proposed to perform many functions in the lungs, such as smooth muscle relaxation, host defense, inhibition of platelet aggregation, and neurotransmission. Exhaled NO concentration is elevated in untreated asthma, reduced by corticosteroid therapy, and elevated during acute exacerbation of asthma relative to results in healthy controls (2,14,19,24). The underlying mechanisms leading to increased NO release are not fully understood but likely involve increased expression of inducible NO synthase in the airway epithelium (8, 10) and nitrite conversion to NO at low pH (13,18,31,32). Acute asthma impairs the ability of the lungs to buffer the breath condensate, resulting in a decrease in the pH of more than two log units (13). This observation may be due to altered expression and activity of glutaminase, which is expressed in both alveolar and airway epithelial cells (12). However, the anatomic location (i.e., airway or alveolar region) of this loss in buffering has not been investigated and could impact potential therapeutic strategies. Our laboratory has previously described a two-compartment (airway and alveolar regions) model of NO exchange (26) and a single-breath technique (27) to char...
BackgroundThis work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement.MethodsA pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement.ResultsThe augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage.ConclusionsWe have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations.
Shelley DA, Puckett JL, George SC. Quantifying proximal and distal sources of NO in asthma using a multicompartment model. J Appl Physiol 108: 821-829, 2010. First published January 21, 2010 doi:10.1152/japplphysiol.00795.2009 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 Ͻ fractional exhaled NO at 50 ml/s Ͻ 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 leastsquares 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. nitric oxide; heterogeneity; sensitivity; phase III slope NITRIC OXIDE (NO) is a free radical present in exhaled breath and is thought to be a marker of inflammation in the lungs (3, 21). Exhaled NO can be elevated in inflammatory diseases, such as asthma, and is reduced after treatment with inhaled corticosteroids (ICS) (17). These observations have generated significant interest in the clinical use of exhaled NO as a noninvasive marker to diagnose and monitor the progression of inflammatory diseases.Elevated NO in asthma has been traditionally attributed to inflammation in the proximal airways; however, recent evidence highlights the importance of peripheral regions (e.g., respiratory bronchioles) in inflammation (13,18,19). Elevated peripheral NO has been associated with increased symptoms and can be resistant to ICS (13). When NO is measured at the mouth during exhalation, the only way to distinguish between the proximal and peripheral NO sources is through a mathematical model. The two-compartment model of NO exchange is a relatively simple, yet powerful, tool to partition the NO signal into proximal (large airways) and distal (small airways and alve...
The current impulse noise criteria for the protection against impulse noise injury do not incorporate an objective measure of hearing protection. A new biomechanically-based model has been developed based on improvement of the Auditory Hazard Assessment Algorithm for the Human (AHAAH) using the integrated cochlear energy (ICE) as the damage risk correlate (DRC). The model parameters have been corrected using the latest literature data. The anomalous dose-response inversion behavior of the AHAAH model was eliminated. The modeling results show that the annular ligament (AL) parameters are the dominant cause of the non-monotonic dose-response behavior of AHAAH. Based on parametric optimization analysis, a 40% reduction of the AL compliance from the AHAAH default value removed the dose-response inversion problem, and this value was found to be within the physiological range when compared with experimental data. The transfer functions from the new model are in good agreement with those of the human ear. A dose-response curve based on ICE was developed using the human walk-up temporary threshold shift (TTS) data. Furthermore, the ICE values calculated for the German rifle noise tests show excellent comparison with the injury outcomes, hence providing a significant independent validation of the improved model. The ICE was found to be the best DRC to both large weapons and small arms noise injury data, covering both protected and unprotected exposures, respectively. The new AHAAH model with ICE as the dose metric is adequate for use as a medical standard against impulse noise injury.
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