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Airway Gas Exchange and Exhaled Biomarkers

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Abstract

During inspiration and expiration, gases traverse the conducting airways as they are transported between the environment and the alveolar region of the lungs. The term “conducting” airways is used broadly as the airway tree is thought largely to provide a conduit for the respiratory gases, oxygen and carbon dioxide. However, despite a significantly smaller surface area, and thicker barrier separating the gas phase from the blood when compared to the alveolar region, the airway tree can participate in gas exchange under special conditions such as high water solubility, high chemical reactivity, or production of the gas within the airway wall tissue. While these conditions do not apply to the respiratory gases, other gases demonstrate substantial exchange of the airways and are of particular importance to the inflammatory response of the lungs, the medical‐legal field, occupational health, metabolic disorders, or protection of the delicate alveolar membrane. Given the significant structural differences between the airways and the alveolar region, the physical determinants that control airway gas exchange are unique and require different models (both experimental and mathematical) to explore. Our improved physiological understanding of airway gas exchange combined with improved analytical methods to detect trace compounds in the exhaled breath provides future opportunities to develop new exhaled biomarkers that are characteristic of pulmonary and systemic conditions. © 2011 American Physiological Society. Compr Physiol 1:1837‐1859, 2011.

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Figure 1. Figure 1.

Major anatomical features of the upper respiratory tract. Gross anatomical structures in the upper respiratory tract including the nasal cavity, conchae, teeth, tongue, uvula, oropharynx, nasopharynx, and larynx. From reference .

Figure 2. Figure 2.

Major anatomical features of the lower respiratory Tract. (A) Schematic of the gross anatomical features of the branching structure of the airway tree, and identifying trachea, main stem bronchi, and major lobar bronchi. (B) Schematic mapping the airways to generation number from the trachea (generation 0) to the respiratory bronchioles and alveoli (generations 17‐23). (C) Cross‐section of trachea at higher magnification demonstrating the layer of the airway wall including the epithelium, cartilage ring, and subepithelial connective tissue. From reference .

Figure 3. Figure 3.

Convection and diffusion in the airways. (A) laminar (solid line) and turbulent (dashed line) flow velocity distributions within a cylinder or tube. The velocity, ν, is normalized by the maximum velocity, (at the centerline), and is plotted as a function of radial position, r, normalized by the radius of the tube, R. The laminar and turbulent flow profiles are described in the text [Eqs. and ]. (B) schematic of the steady‐state concentration profile of a gas across a thin membrane (e.g., the airway wall) of thickness L. The solid line depicts an unreactive gas, while the dashed lines depict progressively more reactive gases that are consumed within the membrane. Symbols are described in the text. (C) Schematic of a turbulent flow profile within a sagittal section of a tube and the corresponding partial pressure profile (solid line) across the tube. The pressure of the gas drops rapidly across the boundary layer and then is constant due to turbulent mixing. The resistance to mass transfer is from the boundary layer and can be characterized by a mass transfer coefficient. Additional details and definition of symbols are provided in the text.

Figure 4. Figure 4.

The exchange ratio (ER) is the ratio of airway gas exchange to the total of airway and alveolar gas exchange. Low‐solubility gases exchange in the alveoli while high‐solubility gases exchange in the airways. Intermediate solubility gases exchange in both the airways and the alveoli. From reference .

Figure 5. Figure 5.

Cross‐sectional area of the airway tree. Cross‐sectional area (log scale) is shown as a function of axial position within the airway tree. The open circles represent experimental data from Weibel , and the dashed line represents an exponential fit: A(z)=A17(z/z17)−2 [Eq. ]. The exponential equation is a good fit between approximately airway generations 5 to 17. The numbers in parentheses represent the airway generation number. The cross‐sectional area as a function of length represents the “trumpet” model of the airway tree.

Figure 6. Figure 6.

Multiple breath nitrogen washout. The nitrogen in the lungs is progressively washed out over the course of 10 to 20 breaths of inspiring pure oxygen (A). Each tidal exhalation results in an exhalation profile represented by three phases (B). The slope of phase III (SIII, change in concentration divided by change in exhaled volume) is determined by linear regression over the region spanning 50% to 90% of the exhaled volume for each breath and provides information on ventilation inhomogeneities. In general, the normalized phase III slope increases with lung turnover (cumulative exhaled volume normalized by the functional residual capacity) or breath number. The normalized phase III slope, SN,III (B), is SIII divided by the mean concentration over the same region, CIII, and can be plotted as a function of lung turnover (C). Then, theoretical calculations demonstrate that the rate of increase in SN,III with lung turnover over the range of 1.5 to 6.0 provides an index of ventilation inhomogeneities in the proximal or conducting airways (airway generations 1‐16) (C). This index is denoted Scond (L−1). Furthermore, an index of ventilation inhomogeneity in the acinar region (airway generations 17‐23) can be extracted from SN,III in the first breath (after subtracting the component due to Scond – height of gray shaded region and equal to Scond multiplied by lung turnover for the first breath) (C). This index is denoted Sacin (L−1) – height of yellow shaded region. As ventilation inhomogeneity increases in the respective regions of the lungs, Scond and Sacin increase.

Figure 7. Figure 7.

Water and temperature profiles in the airway tree. Predicted nondimensional inspiratory temperatures and water vapor concentration profiles during room air breathing at rest plotted as a function of the nondimensional distance, x/L. Room air breathing at rest is defined as an inspiratory flow rate of 300 ml/s, an inspiratory temperature of 23°C, and a relative humidity of 30%. The blood temperature is set at 32°C in the nasal cavity, rising linearly distal to the nasal cavity at a rate of 0.33°C/cm, reaching body core temperature near the carina. Superimposed are the values of air temperature, TA and CA determined experimentally within the human respiratory tract by various researchers. The characteristic length used to nondimensionalize the distance into the airways is measured from the nose to the 18th generation of the Weibel lung . From reference .

Figure 8. Figure 8.

Exhaled ethanol. (A) Experimental exhaled ethanol profiles from healthy adult subjects. The y‐axis is the breath ethanol concentration normalized by the blood ethanol concentration. Note the presence of three phases in the exhalation profile. (B) Control volume used for mass and energy balances in a mathematical model of simultaneous heat, water, and ethanol exchange in the airways. Ethanol source is the blood (right‐hand side). The ethanol can then diffuse through the layers of the airway wall before entering the gas phase of the airway lumen. (C) Steady‐state mathematical predictions of the flux of ethanol from different regions of the upper and lower respiratory tract during tidal breathing (both inspiration and expiration). A positive flux denotes transport of the ethanol from the surface to the airstream. From reference .

Figure 9. Figure 9.

Exhaled nitric oxide. (A) experimental exhaled NO profile and exhalation flow in a healthy adult subject. Note the slightly negative slope of the NO concentration with exhalation volume even when the flow is constant. The mean concentration over a specified volume or time interval is denoted by the plateau concentration (NOplat). (B) Experimental exhaled nitric oxide concentrations from the plateau region of the profile (NOplat) are plotted as a function of the constant exhalation flow for 10 healthy adult subjects. Note the strong inverse dependence between exhaled NO concentration on flow and the significant intersubject variability. From reference .

Figure 10. Figure 10.

Two‐compartment model of nitric oxide (NO) exchange. Schematic of two‐compartment model for NO pulmonary exchange. First compartment represents relatively nonexpansile conducting airways; second compartment represents expansile alveoli. Each compartment is adjacent to a layer of tissue that is capable of producing and consuming NO. Exterior to tissue is a layer of blood that represents bronchial or pulmonary circulation and serves as an infinite sink for NO. E and I, expiratory and inspiratory flow, respectively; CE and CI, expiratory and inspiratory concentration, respectively; CAIR and CALV, airway and alveolar concentration, respectively; VAIR and VALV, airway and alveolar volume, respectively; Jt:g,AIR and Jt:g,ALV, total flux of NO from tissue to air and from alveolar tissue, respectively; t, time; V, volume. From reference .

Figure 11. Figure 11.

Ozone (O3) absorption in the airway tree. Concentration curves from an O3 bolus test breath (A) and Λ‐VP distribution from one subject (B). Absorbed fraction (Λ) represents amount of O3 that does not reappear during exhalation relative to amount inhaled, and penetration VP represents mean airway volume traversed by O3 molecules during inhalation, if they were not absorbed. MB and MR, amounts of O3 inhaled and exhaled, respectively. From reference .

Figure 12. Figure 12.

Exhaled acetone profile. Repeated (six times) single exhalation expirograms, using mass spectrometry, for acetone are shown for a single health adult subject. The concentration in the exhaled breath is normalized by the concentration in the alveolar region determined through isothermal rebreathing. Lag time of the instrument and dead space in the collection apparatus have been accounted for, and note the lack of a phase I indicative of zero dead space and thus significant airway gas exchange. Phase II and a positively sloping phase III, similar to ethanol and other breath biomarkers, are evident. From reference .

Figure 13. Figure 13.

Exhaled ethane profile. Recorded single exhalation expirograms for ethane and CO2. 1a and 2a: expirograms for ethane at a scale of 30 and 2 ppb, respectively. 1b and 2b: corresponding expirograms for CO2. In 1a, three phases (I‐III) of expiration are marked. The additional phase IV belongs to exhaled breath beyond the functional residual volume. The gray line represents a linear regression, which is used to determine the slope of the alveolar plateau. The mean alveolar concentration is labeled with a dot. From reference .



Figure 1.

Major anatomical features of the upper respiratory tract. Gross anatomical structures in the upper respiratory tract including the nasal cavity, conchae, teeth, tongue, uvula, oropharynx, nasopharynx, and larynx. From reference .



Figure 2.

Major anatomical features of the lower respiratory Tract. (A) Schematic of the gross anatomical features of the branching structure of the airway tree, and identifying trachea, main stem bronchi, and major lobar bronchi. (B) Schematic mapping the airways to generation number from the trachea (generation 0) to the respiratory bronchioles and alveoli (generations 17‐23). (C) Cross‐section of trachea at higher magnification demonstrating the layer of the airway wall including the epithelium, cartilage ring, and subepithelial connective tissue. From reference .



Figure 3.

Convection and diffusion in the airways. (A) laminar (solid line) and turbulent (dashed line) flow velocity distributions within a cylinder or tube. The velocity, ν, is normalized by the maximum velocity, (at the centerline), and is plotted as a function of radial position, r, normalized by the radius of the tube, R. The laminar and turbulent flow profiles are described in the text [Eqs. and ]. (B) schematic of the steady‐state concentration profile of a gas across a thin membrane (e.g., the airway wall) of thickness L. The solid line depicts an unreactive gas, while the dashed lines depict progressively more reactive gases that are consumed within the membrane. Symbols are described in the text. (C) Schematic of a turbulent flow profile within a sagittal section of a tube and the corresponding partial pressure profile (solid line) across the tube. The pressure of the gas drops rapidly across the boundary layer and then is constant due to turbulent mixing. The resistance to mass transfer is from the boundary layer and can be characterized by a mass transfer coefficient. Additional details and definition of symbols are provided in the text.



Figure 4.

The exchange ratio (ER) is the ratio of airway gas exchange to the total of airway and alveolar gas exchange. Low‐solubility gases exchange in the alveoli while high‐solubility gases exchange in the airways. Intermediate solubility gases exchange in both the airways and the alveoli. From reference .



Figure 5.

Cross‐sectional area of the airway tree. Cross‐sectional area (log scale) is shown as a function of axial position within the airway tree. The open circles represent experimental data from Weibel , and the dashed line represents an exponential fit: A(z)=A17(z/z17)−2 [Eq. ]. The exponential equation is a good fit between approximately airway generations 5 to 17. The numbers in parentheses represent the airway generation number. The cross‐sectional area as a function of length represents the “trumpet” model of the airway tree.



Figure 6.

Multiple breath nitrogen washout. The nitrogen in the lungs is progressively washed out over the course of 10 to 20 breaths of inspiring pure oxygen (A). Each tidal exhalation results in an exhalation profile represented by three phases (B). The slope of phase III (SIII, change in concentration divided by change in exhaled volume) is determined by linear regression over the region spanning 50% to 90% of the exhaled volume for each breath and provides information on ventilation inhomogeneities. In general, the normalized phase III slope increases with lung turnover (cumulative exhaled volume normalized by the functional residual capacity) or breath number. The normalized phase III slope, SN,III (B), is SIII divided by the mean concentration over the same region, CIII, and can be plotted as a function of lung turnover (C). Then, theoretical calculations demonstrate that the rate of increase in SN,III with lung turnover over the range of 1.5 to 6.0 provides an index of ventilation inhomogeneities in the proximal or conducting airways (airway generations 1‐16) (C). This index is denoted Scond (L−1). Furthermore, an index of ventilation inhomogeneity in the acinar region (airway generations 17‐23) can be extracted from SN,III in the first breath (after subtracting the component due to Scond – height of gray shaded region and equal to Scond multiplied by lung turnover for the first breath) (C). This index is denoted Sacin (L−1) – height of yellow shaded region. As ventilation inhomogeneity increases in the respective regions of the lungs, Scond and Sacin increase.



Figure 7.

Water and temperature profiles in the airway tree. Predicted nondimensional inspiratory temperatures and water vapor concentration profiles during room air breathing at rest plotted as a function of the nondimensional distance, x/L. Room air breathing at rest is defined as an inspiratory flow rate of 300 ml/s, an inspiratory temperature of 23°C, and a relative humidity of 30%. The blood temperature is set at 32°C in the nasal cavity, rising linearly distal to the nasal cavity at a rate of 0.33°C/cm, reaching body core temperature near the carina. Superimposed are the values of air temperature, TA and CA determined experimentally within the human respiratory tract by various researchers. The characteristic length used to nondimensionalize the distance into the airways is measured from the nose to the 18th generation of the Weibel lung . From reference .



Figure 8.

Exhaled ethanol. (A) Experimental exhaled ethanol profiles from healthy adult subjects. The y‐axis is the breath ethanol concentration normalized by the blood ethanol concentration. Note the presence of three phases in the exhalation profile. (B) Control volume used for mass and energy balances in a mathematical model of simultaneous heat, water, and ethanol exchange in the airways. Ethanol source is the blood (right‐hand side). The ethanol can then diffuse through the layers of the airway wall before entering the gas phase of the airway lumen. (C) Steady‐state mathematical predictions of the flux of ethanol from different regions of the upper and lower respiratory tract during tidal breathing (both inspiration and expiration). A positive flux denotes transport of the ethanol from the surface to the airstream. From reference .



Figure 9.

Exhaled nitric oxide. (A) experimental exhaled NO profile and exhalation flow in a healthy adult subject. Note the slightly negative slope of the NO concentration with exhalation volume even when the flow is constant. The mean concentration over a specified volume or time interval is denoted by the plateau concentration (NOplat). (B) Experimental exhaled nitric oxide concentrations from the plateau region of the profile (NOplat) are plotted as a function of the constant exhalation flow for 10 healthy adult subjects. Note the strong inverse dependence between exhaled NO concentration on flow and the significant intersubject variability. From reference .



Figure 10.

Two‐compartment model of nitric oxide (NO) exchange. Schematic of two‐compartment model for NO pulmonary exchange. First compartment represents relatively nonexpansile conducting airways; second compartment represents expansile alveoli. Each compartment is adjacent to a layer of tissue that is capable of producing and consuming NO. Exterior to tissue is a layer of blood that represents bronchial or pulmonary circulation and serves as an infinite sink for NO. E and I, expiratory and inspiratory flow, respectively; CE and CI, expiratory and inspiratory concentration, respectively; CAIR and CALV, airway and alveolar concentration, respectively; VAIR and VALV, airway and alveolar volume, respectively; Jt:g,AIR and Jt:g,ALV, total flux of NO from tissue to air and from alveolar tissue, respectively; t, time; V, volume. From reference .



Figure 11.

Ozone (O3) absorption in the airway tree. Concentration curves from an O3 bolus test breath (A) and Λ‐VP distribution from one subject (B). Absorbed fraction (Λ) represents amount of O3 that does not reappear during exhalation relative to amount inhaled, and penetration VP represents mean airway volume traversed by O3 molecules during inhalation, if they were not absorbed. MB and MR, amounts of O3 inhaled and exhaled, respectively. From reference .



Figure 12.

Exhaled acetone profile. Repeated (six times) single exhalation expirograms, using mass spectrometry, for acetone are shown for a single health adult subject. The concentration in the exhaled breath is normalized by the concentration in the alveolar region determined through isothermal rebreathing. Lag time of the instrument and dead space in the collection apparatus have been accounted for, and note the lack of a phase I indicative of zero dead space and thus significant airway gas exchange. Phase II and a positively sloping phase III, similar to ethanol and other breath biomarkers, are evident. From reference .



Figure 13.

Exhaled ethane profile. Recorded single exhalation expirograms for ethane and CO2. 1a and 2a: expirograms for ethane at a scale of 30 and 2 ppb, respectively. 1b and 2b: corresponding expirograms for CO2. In 1a, three phases (I‐III) of expiration are marked. The additional phase IV belongs to exhaled breath beyond the functional residual volume. The gray line represents a linear regression, which is used to determine the slope of the alveolar plateau. The mean alveolar concentration is labeled with a dot. From reference .

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Steven C. George, Michael P. Hlastala. Airway Gas Exchange and Exhaled Biomarkers. Compr Physiol 2011, 1: 1837-1859. doi: 10.1002/cphy.c090013