The air conditioning in the nose of mammals depends on their mass and on their maximal running speed.

The nose of the mammals is responsible for filtering, humidifying, and heating the air before entering the lower respiratory tract. This conditioning avoids, notably, dehydration of the bronchial and alveolar mucosa. However, since this conditioning is not perfect, exercising in cold air can induce lung inflammation, both for human and non-human mammals. This work aims to compare the air conditioning in the noses of various mammals during inspiration. We build our study on computational fluid dynamics simulations of the heat exchanges in the lumen of the upper respiratory tract of these mammals. These simulations show that the efficiency of the air conditioning in the nose during inspiration does not relate only to the mass m of the mammal but also to its maximal running speed v. More precisely, the results allow establishing a scaling law relating the efficiency of air conditioning in the nose of mammals to the ratio v / log 10 ( m ) . The simulations also correlate the resistance to the flow in the nose to the efficiency of this air conditioning. The obtained scaling law allows predicting the air temperature at the top of the trachea during inspiration for nasal-breathing mammals, and thus notably for humans of various ages.

What Are the Key Anatomical Features for the Success of Nose-to-Brain Delivery? A Study of Powder Deposition in 3D-Printed Nasal Casts.

Nose-to-brain delivery is a promising way to improve the treatment of central nervous system disorders, as it allows the bypassing of the blood-brain barrier. However, it is still largely unknown how the anatomy of the nose can influence the treatment outcome. In this work, we used 3D printing to produce nasal replicas based on 11 different CT scans presenting various anatomical features. Then, for each anatomy and using the Design of Experiments methodology, we characterised the amount of a powder deposited in the olfactory region of the replica as a function of multiple parameters (choice of the nostril, device, orientation angle, and the presence or not of a concomitant inspiration flow). We found that, for each anatomy, the maximum amount of powder that can be deposited in the olfactory region is directly proportional to the total area of this region. More precisely, the results show that, whatever the instillation strategy, if the total area of the olfactory region is below 1500 mm2, no more than 25% of an instilled powder can reach this region. On the other hand, if the total area of the olfactory region is above 3000 mm2, the deposition efficiency reaches 50% with the optimal choice of parameters, whatever the other anatomical characteristics of the nasal cavity. Finally, if the relative difference between the areas of the two sides of the internal nasal valve is larger than 20%, it becomes important to carefully choose the side of instillation. This work, by predicting the amount of powder reaching the olfactory region, provides a tool to evaluate the adequacy of nose-to-brain treatment for a given patient. While the conclusions should be confirmed via in vivo studies, it is a first step towards personalised treatment of neurological pathologies.

Water and heat exchanges in mammalian lungs.

A secondary function of the respiratory system of the mammals is, during inspiration, to heat the air to body temperature and to saturate it with water before it reaches the alveoli. Relying on a mathematical model, we propose a comprehensive analysis of this function, considering all the terrestrial mammals (spanning six orders of magnitude of the body mass, M) and focusing on the sole contribution of the lungs to this air conditioning. The results highlight significant differences between the small and the large mammals, as well as between rest and effort, regarding the spatial distribution of heat and water exchanges in the lungs, and also in terms of regime of mass transfer taking place in the lumen of the airways. Interestingly, the results show that the mammalian lungs appear to be designed just right to fully condition the air at maximal effort (and clearly over-designed at rest, except for the smallest mammals): all generations of the bronchial region of the lungs are mobilized for this purpose, with calculated values of the local evaporation rate of water from the bronchial mucosa that can be very close to the maximal ability of the serous cells to replenish this mucosa with water. For mammals with a mass above a certain threshold ([Formula: see text] kg at rest and [Formula: see text] g at maximal effort), it appears that the maximal value of this evaporation rate scales as [Formula: see text] at rest and [Formula: see text] at maximal effort and that around 40% (at rest) or 50% (at maximal effort) of the water/heat extracted from the lungs during inspiration is returned to the bronchial mucosa during expiration, independently of the mass, due to a subtle coupling between different phenomena. This last result implies that, above these thresholds, the amounts of water and heat extracted from the lungs by the ventilation scale with the mass such as the ventilation rate does (i.e. as [Formula: see text] at rest and [Formula: see text] at maximal effort). Finally, it is worth to mention that these amounts appear to remain limited, but not negligible, when compared to relevant global quantities, even at maximal effort (4-6%).

In vitro Evaluation of Paliperidone Palmitate Loaded Cubosomes Effective for Nasal-to-Brain Delivery.

Introduction: This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast. Methods: Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements. Results: The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively. Conclusion: The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.

Cardiovascular deconditioning and impact of artificial gravity during 60-day head-down bed rest-Insights from 4D flow cardiac MRI.

Microgravity has deleterious effects on the cardiovascular system. We evaluated some parameters of blood flow and vascular stiffness during 60 days of simulated microgravity in head-down tilt (HDT) bed rest. We also tested the hypothesis that daily exposure to 30 min of artificial gravity (1 g) would mitigate these adaptations. 24 healthy subjects (8 women) were evenly distributed in three groups: continuous artificial gravity, intermittent artificial gravity, or control. 4D flow cardiac MRI was acquired in horizontal position before (-9 days), during (5, 21, and 56 days), and after (+4 days) the HDT period. The false discovery rate was set at 0.05. The results are presented as median (first quartile; third quartile). No group or group × time differences were observed so the groups were combined. At the end of the HDT phase, we reported a decrease in the stroke volume allocated to the lower body (-30% [-35%; -22%]) and the upper body (-20% [-30%; +11%]), but in different proportions, reflected by an increased share of blood flow towards the upper body. The aortic pulse wave velocity increased (+16% [+9%; +25%]), and so did other markers of arterial stiffness ( C A V I ; C A V I 0 ). In males, the time-averaged wall shear stress decreased (-13% [-17%; -5%]) and the relative residence time increased (+14% [+5%; +21%]), while these changes were not observed among females. Most of these parameters tended to or returned to baseline after 4 days of recovery. The effects of the artificial gravity countermeasure were not visible. We recommend increasing the load factor, the time of exposure, or combining it with physical exercise. The changes in blood flow confirmed the different adaptations occurring in the upper and lower body, with a larger share of blood volume dedicated to the upper body during (simulated) microgravity. The aorta appeared stiffer during the HDT phase, however all the changes remained subclinical and probably the sole consequence of reversible functional changes caused by reduced blood flow. Interestingly, some wall shear stress markers were more stable in females than in males. No permanent cardiovascular adaptations following 60 days of HDT bed rest were observed.

Validation and Sensitivity analysis for a nasal spray deposition computational model.

Validating numerical models against experimental models of nasal spray deposition is challenging since many aspects must be considered. That being said, it is a critical step in the product development process of nasal spray devices. This work presents the validation process of a nasal deposition model, which demonstrates a high degree of consistency of the numerical model with experimental data when the nasal cavity is segmented into two regions but not into three. Furthermore, by modelling the flow as stationary, the computational cost is drastically reduced while maintaining quality of particle deposition results. Thanks to this reduction, a sensitivity analysis of the numerical model could be performed, consisting of 96 simulations. The objective was to quantify the impact of four inputs: the spray half cone angle, mean spray exit velocity, breakup length from the nozzle exit and the diameter of the nozzle spray device, on the three quantities of interest: the percentage of the accumulated number of particles deposited on the anterior, middle and posterior sections of the nasal cavity. The results of the sensitivity analysis demonstrated that the deposition on anterior and middle sections are sensitive to injection angle and breakup length, and the deposition on posterior section is only, but highly, sensitive to the injection velocity.

Instillation of a Dry Powder in Nasal Casts: Parameters Influencing the Olfactory Deposition With Uni- and Bi-Directional Devices.

Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called "nasal cast") to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.

Is airway damage during physical exercise related to airway dehydration? Inputs from a computational model.

In healthy subjects, at low minute ventilation (V̇e) during physical exercise, the water content and temperature of the airways are well regulated. However, with the increase in V̇e, the bronchial mucosa becomes dehydrated and epithelial damage occurs. Our goal was to demonstrate the correspondence between the ventilatory threshold inducing epithelial damage, measured experimentally, and the dehydration threshold, estimated numerically. In 16 healthy adults, we assessed epithelial damage before and following a 30-min continuous cycling exercise at 70% of maximal work rate, by measuring the variation pre- to postexercise of serum club cell protein (cc16/cr). Blood samples were collected at rest, just at the end of the standardized 10-min warm-up, and immediately, 30 min and 60 min postexercise. Mean V̇e during exercise was kept for analysis. Airway water and heat losses were estimated using a computational model adapted to the experimental conditions and were compared with a literature-based threshold of bronchial dehydration. Eleven participants exceeded the threshold for bronchial dehydration during exercise (group A) and five did not (group B). Compared with post warm-up, the increase in cc16/cr postexercise was significant (mean increase ± SE: 0.48 ± 0.08 ng·L-1 only in group A but not in group B (mean difference ± SE: 0.10 ± 0.04 ng·L-1). This corresponds to an increase of 101 ± 32% [range: 16%-367%] in group A (mean ± SE). Our findings suggest that the use of a computational model may be helpful to estimate an individual dehydration threshold of the airways that is associated with epithelial damage during physical exercise.NEW & NOTEWORTHY Using a computational model for heat and water transfers in the bronchi, we identified a threshold in ventilation during exercise above which airway dehydration is thought to occur. When this threshold was exceeded, epithelial damage was found. This threshold might therefore represent the ventilation upper limit during exercise in susceptible individuals. Our results might help to prevent maladaptation to chronic exercise such as exercise-induced bronchoconstriction or asthma.

Closed-Loop Multiscale Computational Model of Human Blood Circulation. Applications to Ballistocardiography.

Cardiac mechanical activity leads to periodic changes in the distribution of blood throughout the body, which causes micro-oscillations of the body's center of mass and can be measured by ballistocardiography (BCG). However, many of the BCG findings are based on parameters whose origins are poorly understood. Here, we generate simulated multidimensional BCG signals based on a more exhaustive and accurate computational model of blood circulation than previous attempts. This model consists in a closed loop 0D-1D multiscale representation of the human blood circulation. The 0D elements include the cardiac chambers, cardiac valves, arterioles, capillaries, venules, and veins, while the 1D elements include 55 systemic and 57 pulmonary arteries. The simulated multidimensional BCG signal is computed based on the distribution of blood in the different compartments and their anatomical position given by whole-body magnetic resonance angiography on a healthy young subject. We use this model to analyze the elements affecting the BCG signal on its different axes, allowing a better interpretation of clinical records. We also evaluate the impact of filtering and healthy aging on the BCG signal. The results offer a better view of the physiological meaning of BCG, as compared to previous models considering mainly the contribution of the aorta and focusing on longitudinal acceleration BCG. The shape of experimental BCG signals can be reproduced, and their amplitudes are in the range of experimental records. The contributions of the cardiac chambers and the pulmonary circulation are non-negligible, especially on the lateral and transversal components of the velocity BCG signal. The shapes and amplitudes of the BCG waveforms are changing with age, and we propose a scaling law to estimate the pulse wave velocity based on the time intervals between the peaks of the acceleration BCG signal. We also suggest new formulas to estimate the stroke volume and its changes based on the BCG signal expressed in terms of acceleration and kinetic energy.

Comprehensive Analysis of Heat and Water Exchanges in the Human Lungs.

This work presents a new mathematical model of the heat and water exchanges in the human lungs (newborn to adult). This model is based on a local description of the water and energy transports in both the lumen and the surrounding tissues, and is presented in a comprehensive, dimensionless framework with explicitly stated assumptions and a strong physiological background. The model is first used to analyze and quantify the key phenomena and dimensionless numbers governing these heat and water exchanges and then it is applied to an adult in various situations (varying atmospheric conditions, exercising…). The results highlight several interesting physiological elements. They show that the bronchial region of the lungs is able to condition the air in all the considered situations even if, sometimes, for instance when exercising, distal generations have to be involved. The model also shows that these distal generations are super-conditioners. Moreover, the results quantify the key role of the submucosal glands in mucus hydration. They also show that, during expiration, a significant cooling of the air and condensation of water occur along the respiratory tract as the vascularization of the tissues surrounding the airways is not able to maintain these tissues at body temperature during inspiration. Due to the interaction between several phenomena, it appears that the ratio of the amount of water returned to the mucosa during expiration to the amount extracted during inspiration is almost independent of the breathing conditions (around 33%). The results also show that, in acute situations, such as suffering from a pathology with airway dysfunction, when being intubated or when exercising above an intensity threshold, the heat and water exchanges in the lungs may be critical regarding mucus hydration. In proximal generations, the evaporation may overwhelm the ability of the submucosal glands to replenish the airway surface liquid with water. In some situations, the cooling of the mucosa may be very important; it can even become colder than the inspired air, due to evaporative cooling. Finally, the results show that breathing cold air can significantly increase the exchanges between the lungs and the environment, which can be critical regarding disease transmission.

The importance of pre-formulation studies and of 3D-printed nasal casts in the success of a pharmaceutical product intended for nose-to-brain delivery.

This review aims to cement three hot topics in drug delivery: (a) the pre-formulation of new products intended for nose-to-brain delivery; (b) the development of nasal casts for studying the efficacy of potential new nose-to-brain delivery systems at the early of their development (pre-formulation); (c) the use of 3D printing based on a wide variety of materials (transparent, biocompatible, flexible) providing an unprecedented fabrication tool towards personalized medicine by printing nasal cast on-demand based on CT scans of patients. This review intends to show the links between these three subjects. Indeed, the pathway selected to administrate the drug to the brain not only influence the formulation strategies to implement but also the design of the cast, to get the most convincing measures from it. Moreover, the design of the cast himself influences the choice of the 3D-printing technology, which, in its turn, bring more constraints to the nasal replica design. Consequently, the formulation of the drug, the cast preparation and its realisation should be thought of as a whole and not separately.

Analysing vagus nerve spontaneous activity using finite element modelling.

Objective.Finite element modelling has been widely used to understand the effect of stimulation on the nerve fibres. Yet the literature on analysis of spontaneous nerve activity is much scarcer. In this study, we introduce a method based on a finite element model, to analyse spontaneous nerve activity with a typical bipolar electrode recording setup, enabling the identification of spontaneously active fibres. We applied our method to the vagus nerve, which plays a key role in refractory epilepsy.Approach.We developed a 3D model including dynamic action potential (AP) propagation, based on the vagus nerve geometry. The impact of key recording parameters-inter-electrode distance and temperature-and uncontrolled parameters-fibre size and position in the nerve-on the ability to discriminate active fibres were quantified. A specific algorithm was implemented to detect and classify APs from recordings, and tested on six ratin-vivovagus nerve recordings.Main results.Fibre diameters can be discriminated if they are below 3µm and 7µm, respectively for inter-electrode distances of 2 mm and 4 mm. The impact of the position of the fibre inside the nerve on fibre diameter discrimination is limited. The range of active fibres identified by modelling in the vagus nerve of rats is in agreement with ranges found at histology.Significance.The nerve fibre diameter, directly proportional to the AP propagation velocity, is related to a specific physiological function. Estimating the source fibre diameter is thus essential to interpret neural recordings. Among many possible applications, the present method was developed in the context of a project to improve vagus nerve stimulation therapy for epilepsy.

Modeling of the Transport and Exchange of a Gas Species in Lungs With an Asymmetric Branching Pattern. Application to Nitric Oxide.

Over the years, various studies have been dedicated to the mathematical modeling of gas transport and exchange in the lungs. Indeed, the access to the distal region of the lungs with direct measurements is limited and, therefore, models are valuable tools to interpret clinical data and to give more insights into the phenomena taking place in the deepest part of the lungs. In this work, a new computational model of the transport and exchange of a gas species in the human lungs is proposed. It includes (i) a method to generate a lung geometry characterized by an asymmetric branching pattern, based on the values of several parameters that have to be given by the model user, and a method to possibly alter this geometry to mimic lung diseases, (ii) the calculation of the gas flow distribution in this geometry during inspiration or expiration (taking into account the increased resistance to the flow in airways where the flow is non-established), (iii) the evaluation of the exchange fluxes of the gaseous species of interest between the tissues composing the lungs and the lumen, and (iv) the computation of the concentration profile of the exchanged species in the lumen of the tracheobronchial tree. Even if the model is developed in a general framework, a particular attention is given to nitric oxide, as it is not only a gas species of clinical interest, but also a gas species that is both produced in the walls of the airways and consumed within the alveolar region of the lungs. First, the model is presented. Then, several features of the model, applied to lung geometry, gas flow and NO exchange and transport, are discussed, compared to existing works and notably used to give new insights into experimental data available in the literature, regarding diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease.

Experimental Characterization of the Drying of Kampot Red Pepper (Piper nigrum L.).

The objective of this work is to provide new insights into the mechanisms taking place during the drying of the mature grains of Kampot pepper, a cultivar of pepper (Piper nigrum L.), which is produced in the Kampot Province, Cambodia. Indeed, even if the Kampot pepper is recognized for its organoleptic qualities, no research works were dedicated to the drying of its mature grains, in order to yield red pepper. Experiments with different pretreatment and drying conditions were performed. The results of these experiments were analyzed, regarding the drying kinetics, the color of the dry product, and the degradation of the bioactive compounds during the drying. Regarding these bioactive compounds, several parameters were considered: the total phenolic content, the total flavonoid content, and the piperine content. The results show that the Kampot mature pepper is prone to alterations when dried at a temperature of 55∘C or 65∘C: the color, the total phenolic content, and the flavonoid content are significantly altered, while the piperine content, important for the pungency of this spice, seems unaltered. Raising the temperature leads to more important degradations. However, performing a pretreatment by dipping the pepper grains into boiling water appears to significantly reduce these alterations and, concomitantly, to accelerate the drying. As a conclusion of the analysis of the results, it can be stated that, to increase the product quality, it is recommended to pretreat the pepper by dipping it into boiling water during 5 min., before drying at 55∘C.

Cardiovascular adaptation to simulated microgravity and countermeasure efficacy assessed by ballistocardiography and seismocardiography.

Head-down bed rest (HDBR) reproduces the cardiovascular effects of microgravity. We tested the hypothesis that regular high-intensity physical exercise (JUMP) could prevent this cardiovascular deconditioning, which could be detected using seismocardiography (SCG) and ballistocardiography (BCG). 23 healthy males were exposed to 60-day HDBR: 12 in a physical exercise group (JUMP), the others in a control group (CTRL). SCG and BCG were measured during supine controlled breathing protocols. From the linear and rotational SCG/BCG signals, the integral of kinetic energy ([Formula: see text]) was computed on each dimension over the cardiac cycle. At the end of HDBR, BCG rotational [Formula: see text] and SCG transversal [Formula: see text] decreased similarly for all participants (- 40% and - 44%, respectively, p < 0.05), and so did orthostatic tolerance (- 58%, p < 0.01). Resting heart rate decreased in JUMP (- 10%, p < 0.01), but not in CTRL. BCG linear [Formula: see text] decreased in CTRL (- 50%, p < 0.05), but not in JUMP. The changes in the systolic component of BCG linear iK were correlated to those in stroke volume and VO2 max (R = 0.44 and 0.47, respectively, p < 0.05). JUMP was less affected by cardiovascular deconditioning, which could be detected by BCG in agreement with standard markers of the cardiovascular condition. This shows the potential of BCG to easily monitor cardiac deconditioning.

Lifetime of Surface Bubbles in Surfactant Solutions.

Despite the prevalence of surface bubbles in many natural phenomena and engineering applications, the effect of surfactants on their surface residence time is not clear. Numerous experimental studies and theoretical models exist but a clear understanding of the film drainage phenomena is still lacking. In particular, theoretical work predicting the drainage rate of the thin film between a bubble and the free surface in the presence and absence of surfactants usually makes use of the lubrication theory. On the other hand, in numerous natural situations and experimental works, the bubble approaches the free surface from a certain distance and forms a thin film at a later stage. This article attempts to bridge these two approaches. In particular, in this article, we review these works and compare them to our direct numerical simulations where we study the coupled influence of bubble deformation and surfactants on the rising and drainage process of a bubble beneath a free surface. In the present study, the level-set method is used to capture the air-liquid interfaces, and the transport equation of surfactants is solved in an Eulerian framework. The axisymmetric simulations capture the bubble acceleration, deformation, and rest (or drainage) phases from nondeformable to deformable bubbles, as measured by the Bond number (Bo), and from surfactant-free to surfactant-coated bubbles, as measured by the Langmuir number (La). The results show that the distance h between the bubble and the free surface decays exponentially for surfactant-free interfaces (La = 0), and this decay is faster for nondeformable bubbles (Bo ≪ 1) than for deformable ones (Bo ≫ 1). The presence of surfactants (La > 0) slows the decay of h, exponentially for large bubbles (Bo ≫ 1) and algebraically for small ones (Bo ≪ 1). For Bo ≈ 1, the lifetime is the longest and is associated with the (Marangoni) elasticity of the interfaces.

Evaporation versus imbibition in a porous medium.

Predicting and controlling the liquid dynamics in a porous medium is of large importance in numerous technological and industrial situations. We derive here a general analytical solution for the dynamics of a flat liquid front in a porous medium, considering the combined effects of capillary imbibition, gravity and evaporation. We highlight that the dynamics of the liquid front in the porous medium is controlled by two dimensionless numbers: a gravity-capillary number G and an evaporation-capillary number E. We analyze comprehensively the dynamics of the liquid front as functions of G and E, and show that the liquid front can exhibit seven kinds of dynamics classified in three types of behaviors. For each limiting case, a simplified expression of the general solution is also derived. Finally, estimations of G and E are computed to evidence the most common regimes and corresponding liquid front dynamics encountered in usual applied conditions. This is realized by investigating the influence of the liquid and porous medium properties, as well as of the atmospheric conditions, on the values of the dimensionless numbers.

New insights into the mechanisms controlling the bronchial mucus balance.

In this work, we aim to analyze and compare the mechanisms controlling the volume of mucus in the bronchial region of the lungs of a healthy human adult, at rest and in usual atmospheric conditions. This analysis is based on a balance equation for the mucus in an airway, completed by a computational tool aiming at characterizing the evaporation, during respiration, of the water contained in the bronchial mucus. An idealized representation of the lungs, based on Weibel's morphometric model, is used. The results indicate that the mechanisms controlling the volume of mucus in an airway depend on the localization of the airway in the bronchial region of the lungs. In the proximal generations, the volume of mucus in an airway is mainly controlled by the evaporation of the water it contains and the replenishment, with water, of the mucus layer by epithelial cells or the submucosal glands. Nevertheless, cilia beating in this part of the bronchial region remains of fundamental importance to transport the mucus and hence to eliminate dust and pathogens trapped in it. On the other hand, in the distal generations of the bronchial region, the volume of mucus in an airway is mainly controlled by the mucociliary transport and by the absorption of liquid by the epithelium. This absorption is a consequence of the mucus displacement by the cilia along generations with an interface between the epithelium and the airway surface layer of decreasing area. The numerical results obtained are in good agreement with previously published experimental data, thus validating our approach. We also briefly discuss how our results can improve the understanding and, possibly, the treatment of pulmonary diseases.

A new role for the exhaled nitric oxide as a functional marker of peripheral airway caliber changes: a theoretical study.

Although considered as an inflammation marker, exhaled nitric oxide (FENO) was shown to be sensitive to airway caliber changes to such an extent that it might be considered as a marker of them. It is thus important to understand how these changes and their localization mechanically affect the total NO flux penetrating the airway lumen ( JawNO), and hence FENO, independently from any inflammatory status change. In this work, a new model was used. It simulates NO production, consumption, and diffusion inside the airway epithelium, NO excretion from the epithelial wall into the airway lumen and, finally, its axial transport by diffusion and convection in the airway lumen. This model may also consider the possible presence of a fluid layer coating the epithelial wall. Simulations were performed. They show the great sensitivity of JawNO to peripheral airway caliber changes. Moreover, FENO shows distinct behaviors, depending on the location of the caliber change. Considering a bronchodilation, absence of FENO change was associated with dilation of central airways, FENO increase with dilation down to pre-acinar small airways, and FENO decrease with intra-acinar dilation due to the amplification of the back diffusion flux. The presence of a fluid layer was also shown to play a significant role in FENO changes. Altogether, the present work theoretically supports that specific FENO changes in acute situations are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change. NEW & NOTEWORTHY Using a new model of nitric oxide production and transport, allowing realistic simulation of airway caliber change, the present work theoretically supports that specific changes of the molar fraction of nitric oxide in the exhaled air, occurring without any change in the inflammatory status, are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change.

Modeling of the Nitric Oxide Transport in the Human Lungs.

In the human lungs, nitric oxide (NO) acts as a bronchodilatator, by relaxing the bronchial smooth muscles and is closely linked to the inflammatory status of the lungs, owing to its antimicrobial activity. Furthermore, the molar fraction of NO in the exhaled air has been shown to be higher for asthmatic patients than for healthy patients. Multiple models have been developed in order to characterize the NO dynamics in the lungs, owing to their complex structure. Indeed, direct measurements in the lungs are difficult and, therefore, these models are valuable tools to interpret experimental data. In this work, a new model of the NO transport in the human lungs is proposed. It belongs to the family of the morphological models and is based on the morphometric model of Weibel (1963). When compared to models published previously, its main new features are the layered representation of the wall of the airways and the possibility to simulate the influence of bronchoconstriction (BC) and of the presence of mucus on the NO transport in lungs. The model is based on a geometrical description of the lungs, at rest and during a respiratory cycle, coupled with transport equations, written in the layers composing an airway wall and in the lumen of the airways. First, it is checked that the model is able to reproduce experimental information available in the literature. Second, the model is used to discuss some features of the NO transport in healthy and unhealthy lungs. The simulation results are analyzed, especially when BC has occurred in the lungs. For instance, it is shown that BC can have a significant influence on the NO transport in the tissues composing an airway wall. It is also shown that the relation between BC and the molar fraction of NO in the exhaled air is complex. Indeed, BC might lead to an increase or to a decrease of this molar fraction, depending on the extent of the BC and on the possible presence of mucus. This should be confirmed experimentally and might provide an interesting way to characterize the extent of BC in unhealthy patients.