Such exposures over short periods can aggravate respiratory diseases, particularly asthma, leading to respiratory symptoms such as coughing, wheezing or difficulty breathing , hospital admissions and visits to emergency rooms.

Longer exposures to elevated concentrations of NO 2 may contribute to the development of asthma and potentially increase susceptibility to respiratory infections.

People with asthma, as well as children and the elderly are generally at greater risk for the health effects of NO 2. NO 2 along with other NO x reacts with other chemicals in the air to form both particulate matter and ozone. Both of these are also harmful when inhaled due to effects on the respiratory system.

Skip to main content. Nitrogen Dioxide NO2 Pollution. Contact Us. Basic Information about NO2. Inhaled nitric oxide also acts as a pulmonary irritant, causing priming of lung macrophages and oxidative damage to lung epithelial cells.

Nitric oxide has also been reported to protect against oxidative damage induced by other reactive intermediates, including superoxide anion and hydroxyl radical. The dose and timing of nitric oxide administration needs to be ascertained in clinical trials before recommendations can be made regarding its optimal use in patients.

Abstract Nitric oxide is produced by many cell types in the lung and plays an important physiologic role in the regulation of pulmonary vasomotor tone by several known mechanisms. Publication types Research Support, Non-U. A Time evolution of the F E NO, 50 during the expiration phase of a classical respiratory cycle.

Dashed line: measurements on a single healthy patient by Kerckx Solid line: calculated with our model using the parameters values given in Tables 1 , 2 and without considering any BC nor mucus layer.

B F E NO at the end of the expiration phase of a respiratory cycle, as a function of Q ex. Dashed line: measurements on a single healthy patient by Silkoff et al.

C Time evolution of the F E NO, 50 during the expiration phase of a respiratory cycle, calculated with our model using the parameters values given in Tables 1 , 2 and without considering any BC nor mucus layer , for different values of the breath-hold duration time.

D Gaseous NO concentration profile in the lungs, at the end of the inspiration phase and at the end of the expiration phase, calculated with our model using the parameters values given in Tables 1 , 2 and without considering any BC nor mucus layer.

Solid line: NO concentration at the end of the expiration phase. Dashed line: NO concentration at the end of the inspiration phase. A second characteristic of the pulmonary NO transport is related to the link between the expiration flow rate and the value of the F E NO at the end of the respiratory cycle.

It has been experimentally shown that this value of the F E NO decreases when the expiration flow rate increases. In Figure 4B , the value of the F E NO at the end of the expiration phase, calculated by the model for healthy lungs, is presented as a function of Q ex.

The data presented in Tables 1 , 2 have been used to generate these results. It is observed that the expected link between the value of the F E NO at the end of the expiration phase and the expiration flow rate is well reproduced by the model solid line.

In Figure 4B , this link between the expiration flow rate and the value of the F E NO at the end of the respiratory cycle, determined on a single healthy patient by Silkoff et al. A third characteristic of the pulmonary NO transport is related to the link between the duration of a breath-hold phase and the time evolution of the F E NO during the expiration phase of a respiratory cycle Gabbay et al.

When a sufficient long breath-hold phase is realized, the accumulation of the NO in the airways leads to the presence of a maximum in the plot of the F E NO vs. time during the expiration phase: the F E NO quickly rises during a few seconds, until reaching a maximal value.

This maximal value increases if the duration of the breath-hold phase increases. Then, the F E NO rapidly decreases, until reaching a local minimal value. Finally, during the rest of the expiration phase, the F E NO slowly increases Gabbay et al.

In Figure 4C , the time evolution of the F E NO during the expiration phase of a respiratory cycle, calculated with the model for healthy lungs using the parameters values given in Tables 1 , 2 , is presented, for different values of the breath-hold duration time.

It is observed that the expected link between the time evolution of the F E NO and the duration of the breath-hold phase is well reproduced by the model. Several authors also point out different characteristics of the gaseous NO concentration profile in the lungs during a classical respiratory cycle.

In the 2—3 last generations, the gaseous NO concentration remains almost homogeneous and constant during the entire cycle, at a value of approximately 2—3 ppb Pietropaoli et al. This physiological value is the result of a quasi-steady balance between NO production and consumption in these generations.

At the end of the respiration phase, the gaseous NO concentration profile exhibits a maximum approximately at the boundary between the alveolar part and the bronchial part of the lungs i.

At the end of the expiration phase, the gaseous NO concentration is almost constant in generations 0—7 value of approximately 15 ppb. Then, it significantly decreases in the so-called intermediate zone of the lungs generations 8—17 , until reaching a value of approximately 2—3 ppb in the last generations.

It is mentioned in the next section that, starting from generation 16—17, diffusion begins to be the dominant mechanism of gaseous mass transport. As it appears that the gaseous NO concentration gradient in generations 18 to 20 is pointing toward the mouth during the entire respiration cycle, a diffusion flux of NO toward the end of the lungs is permanently taking place in these generations during the cycle even during expiration.

This phenomenon is commonly called back-diffusion Van Muylem et al. In Figure 4D , the gaseous NO concentration profile in the lungs, calculated with our model for healthy lungs, is presented at the end of the inspiration phase and at the end expiration phase of a classical respiratory cycle.

Data presented in Tables 1 , 2 have been used. It shows that the calculated gaseous NO concentration profiles exhibit the characteristics mentioned above.

The use of the model to simulate a respiratory cycle with a short breath hold phase 2 s allows highlighting an interesting feature of gas diffusion in the lungs.

In Figures 5A,B , the gaseous NO concentration profile in healthy lungs, calculated with our model, is presented at the end of a 2 s breath hold phase within a respiratory cycle. Except for t bh , all other parameters values are the ones given in Tables 1 , 2.

It can be observed in Figure 5B that, in the last generations of the lungs, the gaseous NO concentration profile is almost at quasi steady-state at the end of the breath hold phase.

Indeed, diffusion is the only mechanism of gaseous NO mass transport during a breath hold phase and it can be observed in Figure 5B that, in each of these generations, the NO concentration profile is almost linear. On the other hand, it can be observed in Figure 5A that, in the first generations of the lungs, the gaseous NO concentration profile is far from being at quasi steady-state.

Indeed, it can be observed in Figure 5A that, in each of these generations, the NO concentration profile is far from being linear. The concentration gradients remain located near the interface between these generations.

Figure 5. Gaseous NO concentration profile in healthy lungs, calculated with the model, at the end of a 2 s breath hold phase within a respiratory cycle.

A Generations 0—5. B Generations 12— It is also interesting to use the model [including the solutions of Equation 25 with boundary conditions 26 and 27, given in Appendix A ] to analyze the NO concentration profile in the layers composing an airway wall, at different moment of a respiratory cycle.

As it might have been expected, the NO concentration reaches a maximum in the epithelial layer. It means that the NO produced in the epithelial layer is partially transferred to the blood and partially to the gas in the lumen.

Figure 6. The concentration is here reported as a function of the distance to the center of the airway. The NO concentration is here reported as a function of the distance to the center of the airway. Three important dimensionless numbers appear in the model: two Hatta numbers [see Equation 30 ] and the Péclet number [see Equation 36 ].

Two Hatta numbers Ha are defined for each generation. A Ha number compares a characteristic time of NO consumption in a tissue composing an airway wall epithelial layer or muscle layer to a characteristic time of transport by diffusion in this tissue.

The two Ha numbers introduced in this work are proportional to the epithelial layer thickness and to the muscles layer thickness, respectively. In healthy lungs, these thicknesses are the same in each generation, and they experience variations during a respiratory cycle.

Using the model and the data given in Tables 1 , 2 , it can be calculated that these variations are relatively small and that Ha i is around 0. Hence, the NO consumption in the tissues has a moderate influence on the NO concentration profile in these tissues. On the other hand, BC can induce an important relative increase of the thicknesses of the epithelial and muscles layers.

Using the model and the data given in Tables 1 , 2 , it can be calculated that BC can lead to values of Ha i up to 1 and to values of Hã i up to 0. Hence, when BC occurs in a generation, the NO consumption in the tissues in this generation has a stronger influence on the NO concentration profile in these tissues than without BC.

This short analysis shows that BC can have a significant influence on the mechanisms of NO transport in the tissues composing an airway wall. A Péclet number Pe is defined for each generation. It compares a longitudinal convective characteristic time to a longitudinal diffusion characteristic time.

As shown in Table 1 , the value of Pe strongly depends on the generation number. As seen in Equation 36 , Pe is proportional to the length of the generation and inversely proportional to the flow cross-sectional area in the generation when the lungs are at rest.

Thus, Pe decreases when the generation number increases. In the long and large first generations, it appears that Pe is far larger than 1. Hence, the NO transport in the first generations is controlled by convection.

On the other hand, Pe becomes smaller than 1 in the last generations, indicating that the NO transport in these generations is controlled by diffusion. In this section, the model is used to discuss some features of the NO transport in unhealthy lungs.

Several authors showed that the F E NO, 50 is modulated by the level of BC de Gouw et al. For instance, experimental data collected by Verbanck et al. To analyze with our model the NO transport in unhealthy lungs in which BC has occurred and with the possible presence of a mucus layer coating the walls of the airways in some generations , several parameters are introduced in order to compare these unhealthy lungs and the corresponding healthy lungs experiencing a same respiratory cycle i.

Each of these parameters is defined as the relative difference between a property of the unhealthy lungs and the same property for the healthy lungs. These properties are the F E NO, 50 relative difference written Δ F E NO, 50 , the average value of the NO exchange flux density between the epithelial layer and the lumen of the airways in the last generation impacted by the BC and at the end of the expiration phase relative difference written Δ J , and the total flux of NO from the epithelial layer to the lumen of the airways in the last generation impacted by the BC and at the end of the expiration phase relative difference written Δ Flux.

In Figures 7A—C Δ F E NO, 50 , Δ J and Δ Flux are presented for unhealthy lungs in which BC occurred from generation 2 up to a given generation this is called cumulative BC; it is assumed that BC cannot occur in the first two generations , for different values of β, and without any mucus layer.

Homogeneous BC is assumed, i. The parameters values given in Tables 1 , 2 were used to generate these figures.

Figure 7. A Δ F E NO, 50 for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β.

B Δ J for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β. C Δ Flux for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β.

D Δ F E NO, 50 for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β. Generations 0—18 are coated with a mucus layer of 5 μ m thick before constriction.

E Δ J for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β.

F Δ Flux for unhealthy lungs in which BC occurs from generation zero up to a given generation, for different values of β. Generations 0 to 18 are coated with a mucus layer of 5 μ m thick before constriction. It can be observed in Figure 7B that Δ J is positive, whatever the extent of the BC and the value of β.

Moreover, Δ J increases if β increases. If BC occurs in an airway, it does not modify the volume of the epithelium and hence the amount of NO produced per unit time in the airway.

On the other hand, if BC occurs in an airway, it has two opposite effects on the mechanisms of NO transport in the airway wall. First, as mentioned previously, the Hatta numbers of the concerned generation are increased by BC.

It tends to decrease the NO concentration gradient at the interface between the epithelial layer and the lumen. Second, the increase of the muscles and epithelial layers thicknesses leads to an increase of the residence time of the produced NO in the airway wall.

Therefore, BC tends to increase the NO concentration in the layers composing the airway wall see Figure 6B. Moreover, as diffusion is the mechanism of mass transport in the airway wall, a characteristic time of this mass transport is proportional to the square of the wall thickness.

Therefore, BC tends to increase the ratio of the maximal NO concentration in the airway wall to the wall thickness, and thus the NO concentration gradient at the interface between the epithelial layer and the lumen. This effect can also be understood by noting that, when solving an 1D diffusion equation in a slab, with a constant volumetric production term and concentrations equal to zero at the slab extremities, it is calculated that the maximal concentration in the slab is proportional to the square of the slab thickness and that the concentration gradient at the slab extremities are proportional to the slab thickness.

As Δ J is calculated as being positive, it appears that the first of these effects is overwhelmed by the second one due to the low values of the Hatta numbers. The effect of BC on the NO concentration profile in the layers composing an airway wall can be be observed in Figure 6B.

In Figure 6B , these profiles are compared with the corresponding ones in healthy lungs. Data presented in Tables 1 , 2 have been used to generation these profiles. It can be observed in Figure 7C that Δ Flux is negative, whatever the extent of the BC and the value of β. It means that, in the generations impacted by the BC, the decrease of the exchange surface between the epithelium and the lumen does more than compensate the above mentioned increase of the NO exchange flux density between the epithelial layer and the lumen of the airways.

This might have been expected when looking at the results presented in Figure 7B. It can be observed in Figure 7A that, as expected, cumulative BC influences the F E NO, When cumulative BC is limited to the so-called proximal zone of the lungs generations 0 to 7 , Δ F E NO, 50 is close to zero; the F E NO, 50 is almost unaffected by the BC.

It can be explained by the fact that the total amount of NO produced in these generations is small, when compared to the total NO production in the lungs.

Indeed, the total volume of the epithelial layers in the generations 0—7 is approximately 0. As a consequence, when it occurs only in the proximal zone of the lungs, BC almost does not affect the F E NO, When cumulative BC extends up to the so-called central and distal zones of the lungs generations 8—16 , it results in a decrease of the F E NO, 50 negative values of Δ F E NO, This is coherent with the results of Verbanck et al.

It can be explained by the fact that a significant part of the total NO production takes place in generations 8— As a consequence, when BC occurs in these generations, it can significantly decrease the F E NO, 50 , due to the fact that, as mentioned previously BC leads to a decrease of the total flux of NO from the epithelial layer to the lumen of the airways in the generations impacted by the BC.

Finally, when cumulative BC extends beyond generation 16, it appears that the F E NO, 50 is increased positive values of Δ F E NO, This can be attributed to the fact that, when BC extends beyond generation 16, it blocks the back-diffusion of the NO, and thus promotes the transport of the produced NO toward the mouth.

This more than compensates the decrease of the total flux of NO from the epithelial layer to the lumen of the airways in the generations impacted by the BC. In Figures 7D—F , Δ F E NO, 50 , Δ J and Δ Flux are presented for unhealthy lungs in which BC occurred from generation 0 up to a given generation, for different values of β, and with a mucus layer of 5 μm thick before BC in the airways up to generation Homogeneous BC is assumed again.

It is observed that the presence of mucus layers leads to a decrease of Δ F E NO, 50 , Δ J and Δ Flux , when compared to the results presented in Figures 7A—C. It seems logical, as the mucus acts as a physical barrier between the site of the NO production the epithelium and the lumen.

It is interesting to note that, depending on the value of β and of the thickness of the mucus layer coating the airways, Δ J can be positive or negative see Figure 7E.

In conclusion, the use of our model shows that the relation between BC and F E NO, 50 is complex. It indicates that BC might lead to an increase or to a decrease of the F E NO, 50 , depending on the extent of the BC and on the possible presence of mucus.

As mentioned previously, in order to determine Equations 29 and 31 , allowing to express J air, i in the presence or in the absence of mucus layers in generation i, two main assumptions are made, regarding the transport of NO in the layers composing the wall of the airways in this generation:.

The first assumption gives accurate results for a given generation if the radius of the lumen of the airways in this generation is at least one order of magnitude larger than the thicknesses of the layers composing the airways walls.

The second assumption gives accurate results for a given respiratory cycle if the characteristic times of the NO transport by diffusion in the layers composing an airway wall t D are at least one order of magnitude smaller than the inspiration and expiration times of the cycle.

For a classical respiratory cycle see Table 2 , t D is thus indeed at least an order of magnitude smaller than the inspiration and expiration times. In order to check more precisely if these two assumptions are appropriate, we have simulated numerically the NO transport in the epithelial and muscles layers of an airway in a given generation in lungs at rest, in response to a sudden increase from 0 to 5 ppb of the NO concentration in the lumen.

The airway wall was considered as being a hollow cylinder i. Data given in Table 2 have been used. In this work, a new model of the NO transport in the human lungs is presented and used. It belongs to the family of the so-called morphological models and it is based on the morphometric model of Weibel Weibel, When compared to previous models, its main new features are the layered, time-dependent, representation of the wall of the airways and the possibility to simulate the influence of bronchoconstriction and of the presence of mucus on the NO transport in lungs.

Furthermore, the model is developed in a dimensionless form. It brings out typical dimensionless numbers such as Péclet and Hatta numbers. It has been checked that the model is able to reproduce experimental information available in the literature.

The model has been used to discuss some features of the NO transport in healthy and unhealthy lungs. The simulation results were analyzed, in order to give new insights into the NO transport in the human lungs, especially when BC has occurred in the lungs.

For instance, it has been shown that BC can have a significant influence on the NO transport in the tissues composing an airway wall. BC increases the NO exchange flux density between the epithelial layer and the lumen of an airway due to the increase of the epithelial and muscles layers thicknesses but decreases the total flux of NO from the epithelial layer to the lumen of an airway due to the decrease of the exchange surface.

It has also been shown that the relation between BC and F E NO, 50 is complex. CK, BH, and AV designed the main characteristics of this article. CK and BH constructed the new proposed model based on the one of AV. CK and BH wrote the article. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors gratefully acknowledge financial support of ESA and BELSPO ESA-ESTEC-PRODEX arrangement American Thoracic Society European Respiratory Society Care Med. doi: PubMed Abstract CrossRef Full Text.

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