Comprehensive Physiology Wiley Online Library

Asthma and Lung Mechanics

Full Article on Wiley Online Library



Abstract

This article will discuss in detail the pathophysiology of asthma from the point of view of lung mechanics. In particular, we will explain how asthma is more than just airflow limitation resulting from airway narrowing but in fact involves multiple consequences of airway narrowing, including ventilation heterogeneity, airway closure, and airway hyperresponsiveness. In addition, the relationship between the airway and surrounding lung parenchyma is thought to be critically important in asthma, especially as related to the response to deep inspiration. Furthermore, dynamic changes in lung mechanics over time may yield important information about asthma stability, as well as potentially provide a window into future disease control. All of these features of mechanical properties of the lung in asthma will be explained by providing evidence from multiple investigative methods, including not only traditional pulmonary function testing but also more sophisticated techniques such as forced oscillation, multiple breath nitrogen washout, and different imaging modalities. Throughout the article, we will link the lung mechanical features of asthma to clinical manifestations of asthma symptoms, severity, and control. © 2020 American Physiological Society. Compr Physiol 10:975‐1007, 2020.

Figure 1. Figure 1. Illustration of major inflammatory mechanisms involved in asthma pathogenesis. The healthy airway is depicted at the top, with airways smooth muscle surrounding the airway epithelium sitting on the reticular basement membrane. Moving counterclockwise, eosinophilic asthma is seen by increased eosinophilic inflammation driven by allergen stimulation resulting in increased eosinophilic and mast cell activation. Next is seen nonallergic eosinophilic inflammation driven by pollutants and microbes also resulting in increased eosinophilic inflammation activation. In the lower right section is seen Type 1 and Type 17 neutrophilic inflammation, driven by pollutants, microbes, and oxidative stress, resulting in increased neutrophil activation. Non‐eosinophilic asthma may also be paucigranulocytic (top right), with few inflammatory cells, or mixed granulocytic, with both eosinophilic and neutrophilic inflammation (bottom). Reused, with permission, from Papi A, et al., 2018 210.
Figure 2. Figure 2. Illustration of key factors determining airway narrowing. Airway caliber is regulated by surrounding airway smooth muscle force balanced against parenchymal tethering. Other factors that modulate airway caliber include the thickness of the airway wall due to inflammation, edema and remodeling, mucosal folding, the geometric amplification of airway narrowing by the presence of increased mucus and airway lining fluid (red), and the elastic properties of the airway wall. Modified, with permission, from Harvey BC and Lutchen KR, 2013 109.
Figure 3. Figure 3. Illustration of the effects of deep inspiration (DI) on airway size based on the concept of relative hysteresis of airway and lung parenchyma. (A) Airway and lung pressure versus volume curves showing equal hysteresis of airway and lung, as seen by the area within the P‐V curves. In this circumstance, a deep inspiration results in no change in airway caliber, as seen by the symmetrical balance of pressure for a given volume on the left, and the equal diameters of the airways on the right. (B) PV curves showing airway greater than parenchymal hysteresis, which results in a bronchodilator response to deep inspiration, as seen by the greater dilator force after inhalation. (C) PV curves showing parenchymal greater than airway hysteresis, which results in a bronchoconstrictor response to deep inspiration, as seen by the greater constrictor force after inspiration. Reused, with permission, from Pellegrino R, et al., 1998 222.
Figure 4. Figure 4. Diagram illustrating fluctuations in peak flow over time. This recording shows fluctuating peak flow measured twice daily over 150 days. The statistical pattern of fluctuation is similar at different time scales, as seen by the inset showing magnification of a shorter time period, illustrating the fractal properties of this time series. Reused, with permission, from Frey U and Suki B, 2008 85.
Figure 5. Figure 5. Single‐breath nitrogen washout trace from a healthy 21‐year‐old male without respiratory disease. Participant inhaled 100% O2 from residual volume (RV) to total lung capacity (TLC) and then expired from TLC to RV. The expiratory nitrogen trace is comprised of four distinct phases: Phase I (dead space), Phase II (bronchial ventilation), Phase III (alveolar ventilation), and Phase IV (sudden increase indicating onset of airway closure). Closing volume (CV, blue bar) is the expired volume between the onset Phase IV and RV. Closing capacity (CC) is calculated as CV + RV. The slope of Phase III is plotted between 25% and 75% of vital capacity (orange dashed line). Note the unconventional x‐axis in which volume been plotted based on total lung capacity measured by body plethysmography to show CC and RV.
Figure 6. Figure 6. Illustration of the effects of homogeneous versus heterogeneous airway constriction on lung resistance (RL) and elastance (EL) measured by the forced oscillation technique. (A) Resistance (R) is plotted against frequency and compared between the healthy state and different states of airway constriction. Under conditions of homogeneous constriction, there is relatively uniform elevation of R across the frequency range. Under conditions of heterogeneous constriction, there is considerable frequency dependence, with R at lower frequencies being markedly elevated. (B) Effects of different airway constriction patterns on elastance (E) relative to the healthy state. (Note that only E is plotted, not inertance, which also contributes to reactance.) Homogeneous constriction causes most of the oscillatory input signal to be shunted into the central airways, resulting in a progressive increase of E with frequency. Heterogeneous airway constriction results in a marked rise in E with a jump in E at breathing frequency reflecting airway closure. Reused, with permission, from Lui JK and Lutchen KR, 2017 170.
Figure 7. Figure 7. De‐recruitment measured by forced oscillation technique in a 21‐year‐old healthy male without respiratory disease. The participant performed a slow vital capacity during which respiratory system reactance (Xrs) was continuously measured and the points of de‐recruitment (DR1, diamond; DR2, circle) calculated as previously described 199. Note that functional residual capacity (FRC) occurs above both de‐recruitment points and that closing capacity (CC) measured from the single‐breath nitrogen washout test occurs at approximately the same volume as DR2.
Figure 8. Figure 8. Imaging of heterogeneous ventilation by hyperpolarized helium (3He)‐MRI. Shown in this example are the ventilation images obtained from a healthy subject (A), compared to three different subjects with mild (B), moderate (C), and severe (D) asthma. Notice the increasing number of ventilation defects (white arrows), reflecting functional airway closure, as asthma becomes more severe. Reused, with permission, from Samee S, et al., 2003 242.
Figure 9. Figure 9. Imaging of heterogeneous ventilation by ventilation SPECT/CT. Shown are the images from one subject before (left) and after (right) methacholine. Not only are there larger and new poorly ventilated or non‐ventilated spaces (black), but the ventilation has become more heterogeneous within the ventilated airspaces, as seen by the color coding of ventilation and the histogram distribution of ventilation below the images. Reused, with permission, from Farrow CE, et al., 2017 80.
Figure 10. Figure 10. Nitrogen trace from a multiple breath nitrogen washout test. The participant was instructed to take tidal volume breaths of approximately 1 liter until end‐expiratory nitrogen concentration had fallen by 1/40th of the initial concentration (∼2.5%). Lung clearance index (LCI) is calculated as the lung turnover (cumulative expired volume/functional residual capacity) at this point. Insets show the Phase III slope normalized by the mean expiratory nitrogen concentration for the 1st and 25th breaths, respectively.
Figure 11. Figure 11. Derivation of two parameters of ventilation heterogeneity from the multiple breath nitrogen washout test. The slope of the plot between lung turnovers 1.5 and 6 reflects ventilation heterogeneity occurring in airways where gas transport is dependent upon convection. This slope is termed Scond as it is felt to represent ventilation at the level of the peripheral conducting airways. The (normalized) Phase III slope of the first breath (minus the contribution of Scond, that is, Scond × lung turnover at first breath) reflects ventilation heterogeneity at the interface between convection and diffusion gas transport, known as the diffusion front. This is felt to represent the heterogeneity of the ventilation at the entrance to the acinar region and is termed Sacin. Data are shown from a 34‐year‐old male with normal lung function (Δ) and a 45‐year‐old female with asthma (○).
Figure 12. Figure 12. Illustration of anatomic areas of involvement in determining conduction‐dependent and diffusive‐conductive dependent ventilation. While not meant to precisely indicate anatomic location, Scond is seen to arise in more proximal conducting airways, and Sacin is seen to arise in more distal airways at the junction between conductive and acinar ventilation. Reused, with permission, from Verbanck S and Paiva M, 2011 291.
Figure 13. Figure 13. Parallel and serial airway interdependence leading to heterogeneous ventilation. This illustration depicts a symmetrically bifurcating airway tree under uniform ASM constriction (red lightning bolts). On the left is illustrated the consequences of parallel interdependence of airways on ventilation. One airway has a slightly thicker airway wall than the other (red area). Accordingly, during ASM constriction, airflow is reduced more to this airway (dashed blue arrow) than its daughter branching airway (solid blue arrow). The reduced airflow leads to reduced distal ventilation, and hence reduced expansion of the surrounding lung parenchyma. This leads to reduced tethering forces on the embeddedairway (purple arrows), allowing less stretch of the ASM, and therefore enhancing its constriction. This pattern results in a vicious cycle (curving green arrows) culminating in widespread loss of ventilation to the parenchyma fed by that airway (catastrophic airway collapse). This is seen as a ventilation defect seen on imaging (Vdef). Meanwhile, under conditions of conserved total minute ventilation, airflow is diverted away from the thickened airway into the daughter airway without airway wall thickening (thicker blue arrow) increasing ventilation to the parenchyma served by that airway. This results in increased expansion of that parenchymal area with consequent increased tethering forces and increased tidal ASM stretch and dilation of the airway. This process also cycles until a dynamic equilibrium of airway size and parenchymal expansion is reached. On the right is shown the consequences of serial interdependence of airways. Transmural pressure across the airway is greater for central than peripheral airways during tidal breathing, such that under conditions of uniform ASM constriction, central airways are stretched more during tidal breathing than peripheral airways, resulting in a net greater narrowing of peripheral airways than central airways. The end result may once again be ventilation defects seen on imaging. Adapted, with permission, from Winkler T and Suki B, 2011 309.
Figure 14. Figure 14. Illustration of airways hyperresponsiveness based on dose‐response curves relating FEV1 to methacholine concentration. The normal subject is characterized by bronchoconstriction to methacholine only at high doses, with a 20% fall in FEV1 occurring above 64 mg/mL and a plateau at higher levels. The mild asthmatic is hyperresponsive to methacholine, as seen by the upward (increased response) and leftward (increased sensitivity) shift of the dose‐response curve, resulting in a PC20 of 4 mg/mL, and no clear plateau. The severe asthmatic has even more hyperresponsiveness, with a further shift up and to the left of the dose‐response curve resulting in a PC20 of 1 mg/mL and no plateau. Reused, with permission, from O'Byrne PM, et al., 2009 203.
Figure 15. Figure 15. Pathways involved in direct and indirect airways hyperresponsiveness. On the left is depicted the events occurring in exercise or hyperpnea‐induced bronchoconstriction, where respiratory water loss results in increased osmolarity of the airway surface liquid, which stimulates mediator release from mast cells and eosinophils, resulting in airway smooth muscle (ASM) constriction. On the right are the events involved in allergen challenge, where the allergen‐IgE complex activates cellular inflammation and subsequent ASM constriction. Both exercise/hyperpnea and allergen challenges (or hypertonic saline, mannitol, or adenosine monophosphate) are considered indirect challenges because they stimulate ASM constriction indirectly via proximal mediators and events. This is in contrast to methacholine or histamine challenge, which results in direct stimulation of ASM. Reused, with permission, from O'Byrne PM, et al., 2009 203.
Figure 16. Figure 16. Mechanisms involved in airways hyperresponsiveness. Multiple factors govern airway responsiveness, including ASM contractility, mechanical load on ASM (opposing or enhancing ASM constriction), geometry of the airway (amplifying ASM constriction), and delivery of the agonist (enhancing the sensitivity to agonist). In addition, not shown directly, heterogeneity of airway constriction throughout the lung also contributes to responsiveness. Reused, with permission, from Bates JH, 2016 14.
Figure 17. Figure 17. Summary illustration of influence of altered lung mechanics on clinical manifestations of asthma. This highly schematic summary reminds us that many aspects of lung mechanics are involved in the clinical manifestations of asthma as measured by asthma severity and asthma control. These include increased airway resistance due to multiple factors governing airway caliber, including airway smooth muscle tone, airway wall thickness and stiffness, surrounding lung elastic recoil and airway‐parenchymal interdependence. Subsequent effects include airflow limitation, gas trapping, ventilation heterogeneity, and airway hyperresponsiveness. Adapted, with permission, from O'Toole J, 2016 209.


Figure 1. Illustration of major inflammatory mechanisms involved in asthma pathogenesis. The healthy airway is depicted at the top, with airways smooth muscle surrounding the airway epithelium sitting on the reticular basement membrane. Moving counterclockwise, eosinophilic asthma is seen by increased eosinophilic inflammation driven by allergen stimulation resulting in increased eosinophilic and mast cell activation. Next is seen nonallergic eosinophilic inflammation driven by pollutants and microbes also resulting in increased eosinophilic inflammation activation. In the lower right section is seen Type 1 and Type 17 neutrophilic inflammation, driven by pollutants, microbes, and oxidative stress, resulting in increased neutrophil activation. Non‐eosinophilic asthma may also be paucigranulocytic (top right), with few inflammatory cells, or mixed granulocytic, with both eosinophilic and neutrophilic inflammation (bottom). Reused, with permission, from Papi A, et al., 2018 210.


Figure 2. Illustration of key factors determining airway narrowing. Airway caliber is regulated by surrounding airway smooth muscle force balanced against parenchymal tethering. Other factors that modulate airway caliber include the thickness of the airway wall due to inflammation, edema and remodeling, mucosal folding, the geometric amplification of airway narrowing by the presence of increased mucus and airway lining fluid (red), and the elastic properties of the airway wall. Modified, with permission, from Harvey BC and Lutchen KR, 2013 109.


Figure 3. Illustration of the effects of deep inspiration (DI) on airway size based on the concept of relative hysteresis of airway and lung parenchyma. (A) Airway and lung pressure versus volume curves showing equal hysteresis of airway and lung, as seen by the area within the P‐V curves. In this circumstance, a deep inspiration results in no change in airway caliber, as seen by the symmetrical balance of pressure for a given volume on the left, and the equal diameters of the airways on the right. (B) PV curves showing airway greater than parenchymal hysteresis, which results in a bronchodilator response to deep inspiration, as seen by the greater dilator force after inhalation. (C) PV curves showing parenchymal greater than airway hysteresis, which results in a bronchoconstrictor response to deep inspiration, as seen by the greater constrictor force after inspiration. Reused, with permission, from Pellegrino R, et al., 1998 222.


Figure 4. Diagram illustrating fluctuations in peak flow over time. This recording shows fluctuating peak flow measured twice daily over 150 days. The statistical pattern of fluctuation is similar at different time scales, as seen by the inset showing magnification of a shorter time period, illustrating the fractal properties of this time series. Reused, with permission, from Frey U and Suki B, 2008 85.


Figure 5. Single‐breath nitrogen washout trace from a healthy 21‐year‐old male without respiratory disease. Participant inhaled 100% O2 from residual volume (RV) to total lung capacity (TLC) and then expired from TLC to RV. The expiratory nitrogen trace is comprised of four distinct phases: Phase I (dead space), Phase II (bronchial ventilation), Phase III (alveolar ventilation), and Phase IV (sudden increase indicating onset of airway closure). Closing volume (CV, blue bar) is the expired volume between the onset Phase IV and RV. Closing capacity (CC) is calculated as CV + RV. The slope of Phase III is plotted between 25% and 75% of vital capacity (orange dashed line). Note the unconventional x‐axis in which volume been plotted based on total lung capacity measured by body plethysmography to show CC and RV.


Figure 6. Illustration of the effects of homogeneous versus heterogeneous airway constriction on lung resistance (RL) and elastance (EL) measured by the forced oscillation technique. (A) Resistance (R) is plotted against frequency and compared between the healthy state and different states of airway constriction. Under conditions of homogeneous constriction, there is relatively uniform elevation of R across the frequency range. Under conditions of heterogeneous constriction, there is considerable frequency dependence, with R at lower frequencies being markedly elevated. (B) Effects of different airway constriction patterns on elastance (E) relative to the healthy state. (Note that only E is plotted, not inertance, which also contributes to reactance.) Homogeneous constriction causes most of the oscillatory input signal to be shunted into the central airways, resulting in a progressive increase of E with frequency. Heterogeneous airway constriction results in a marked rise in E with a jump in E at breathing frequency reflecting airway closure. Reused, with permission, from Lui JK and Lutchen KR, 2017 170.


Figure 7. De‐recruitment measured by forced oscillation technique in a 21‐year‐old healthy male without respiratory disease. The participant performed a slow vital capacity during which respiratory system reactance (Xrs) was continuously measured and the points of de‐recruitment (DR1, diamond; DR2, circle) calculated as previously described 199. Note that functional residual capacity (FRC) occurs above both de‐recruitment points and that closing capacity (CC) measured from the single‐breath nitrogen washout test occurs at approximately the same volume as DR2.


Figure 8. Imaging of heterogeneous ventilation by hyperpolarized helium (3He)‐MRI. Shown in this example are the ventilation images obtained from a healthy subject (A), compared to three different subjects with mild (B), moderate (C), and severe (D) asthma. Notice the increasing number of ventilation defects (white arrows), reflecting functional airway closure, as asthma becomes more severe. Reused, with permission, from Samee S, et al., 2003 242.


Figure 9. Imaging of heterogeneous ventilation by ventilation SPECT/CT. Shown are the images from one subject before (left) and after (right) methacholine. Not only are there larger and new poorly ventilated or non‐ventilated spaces (black), but the ventilation has become more heterogeneous within the ventilated airspaces, as seen by the color coding of ventilation and the histogram distribution of ventilation below the images. Reused, with permission, from Farrow CE, et al., 2017 80.


Figure 10. Nitrogen trace from a multiple breath nitrogen washout test. The participant was instructed to take tidal volume breaths of approximately 1 liter until end‐expiratory nitrogen concentration had fallen by 1/40th of the initial concentration (∼2.5%). Lung clearance index (LCI) is calculated as the lung turnover (cumulative expired volume/functional residual capacity) at this point. Insets show the Phase III slope normalized by the mean expiratory nitrogen concentration for the 1st and 25th breaths, respectively.


Figure 11. Derivation of two parameters of ventilation heterogeneity from the multiple breath nitrogen washout test. The slope of the plot between lung turnovers 1.5 and 6 reflects ventilation heterogeneity occurring in airways where gas transport is dependent upon convection. This slope is termed Scond as it is felt to represent ventilation at the level of the peripheral conducting airways. The (normalized) Phase III slope of the first breath (minus the contribution of Scond, that is, Scond × lung turnover at first breath) reflects ventilation heterogeneity at the interface between convection and diffusion gas transport, known as the diffusion front. This is felt to represent the heterogeneity of the ventilation at the entrance to the acinar region and is termed Sacin. Data are shown from a 34‐year‐old male with normal lung function (Δ) and a 45‐year‐old female with asthma (○).


Figure 12. Illustration of anatomic areas of involvement in determining conduction‐dependent and diffusive‐conductive dependent ventilation. While not meant to precisely indicate anatomic location, Scond is seen to arise in more proximal conducting airways, and Sacin is seen to arise in more distal airways at the junction between conductive and acinar ventilation. Reused, with permission, from Verbanck S and Paiva M, 2011 291.


Figure 13. Parallel and serial airway interdependence leading to heterogeneous ventilation. This illustration depicts a symmetrically bifurcating airway tree under uniform ASM constriction (red lightning bolts). On the left is illustrated the consequences of parallel interdependence of airways on ventilation. One airway has a slightly thicker airway wall than the other (red area). Accordingly, during ASM constriction, airflow is reduced more to this airway (dashed blue arrow) than its daughter branching airway (solid blue arrow). The reduced airflow leads to reduced distal ventilation, and hence reduced expansion of the surrounding lung parenchyma. This leads to reduced tethering forces on the embeddedairway (purple arrows), allowing less stretch of the ASM, and therefore enhancing its constriction. This pattern results in a vicious cycle (curving green arrows) culminating in widespread loss of ventilation to the parenchyma fed by that airway (catastrophic airway collapse). This is seen as a ventilation defect seen on imaging (Vdef). Meanwhile, under conditions of conserved total minute ventilation, airflow is diverted away from the thickened airway into the daughter airway without airway wall thickening (thicker blue arrow) increasing ventilation to the parenchyma served by that airway. This results in increased expansion of that parenchymal area with consequent increased tethering forces and increased tidal ASM stretch and dilation of the airway. This process also cycles until a dynamic equilibrium of airway size and parenchymal expansion is reached. On the right is shown the consequences of serial interdependence of airways. Transmural pressure across the airway is greater for central than peripheral airways during tidal breathing, such that under conditions of uniform ASM constriction, central airways are stretched more during tidal breathing than peripheral airways, resulting in a net greater narrowing of peripheral airways than central airways. The end result may once again be ventilation defects seen on imaging. Adapted, with permission, from Winkler T and Suki B, 2011 309.


Figure 14. Illustration of airways hyperresponsiveness based on dose‐response curves relating FEV1 to methacholine concentration. The normal subject is characterized by bronchoconstriction to methacholine only at high doses, with a 20% fall in FEV1 occurring above 64 mg/mL and a plateau at higher levels. The mild asthmatic is hyperresponsive to methacholine, as seen by the upward (increased response) and leftward (increased sensitivity) shift of the dose‐response curve, resulting in a PC20 of 4 mg/mL, and no clear plateau. The severe asthmatic has even more hyperresponsiveness, with a further shift up and to the left of the dose‐response curve resulting in a PC20 of 1 mg/mL and no plateau. Reused, with permission, from O'Byrne PM, et al., 2009 203.


Figure 15. Pathways involved in direct and indirect airways hyperresponsiveness. On the left is depicted the events occurring in exercise or hyperpnea‐induced bronchoconstriction, where respiratory water loss results in increased osmolarity of the airway surface liquid, which stimulates mediator release from mast cells and eosinophils, resulting in airway smooth muscle (ASM) constriction. On the right are the events involved in allergen challenge, where the allergen‐IgE complex activates cellular inflammation and subsequent ASM constriction. Both exercise/hyperpnea and allergen challenges (or hypertonic saline, mannitol, or adenosine monophosphate) are considered indirect challenges because they stimulate ASM constriction indirectly via proximal mediators and events. This is in contrast to methacholine or histamine challenge, which results in direct stimulation of ASM. Reused, with permission, from O'Byrne PM, et al., 2009 203.


Figure 16. Mechanisms involved in airways hyperresponsiveness. Multiple factors govern airway responsiveness, including ASM contractility, mechanical load on ASM (opposing or enhancing ASM constriction), geometry of the airway (amplifying ASM constriction), and delivery of the agonist (enhancing the sensitivity to agonist). In addition, not shown directly, heterogeneity of airway constriction throughout the lung also contributes to responsiveness. Reused, with permission, from Bates JH, 2016 14.


Figure 17. Summary illustration of influence of altered lung mechanics on clinical manifestations of asthma. This highly schematic summary reminds us that many aspects of lung mechanics are involved in the clinical manifestations of asthma as measured by asthma severity and asthma control. These include increased airway resistance due to multiple factors governing airway caliber, including airway smooth muscle tone, airway wall thickness and stiffness, surrounding lung elastic recoil and airway‐parenchymal interdependence. Subsequent effects include airflow limitation, gas trapping, ventilation heterogeneity, and airway hyperresponsiveness. Adapted, with permission, from O'Toole J, 2016 209.
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David A. Kaminsky, David G. Chapman. Asthma and Lung Mechanics. Compr Physiol null, 10: 975-1007. doi: 10.1002/cphy.c190020