Interaction between Parenchyma and Airways in Chronic Obstructive Pulmonary Disease and in Asthma1,2 N. B. PRIDE, R. H. INGRAM, JR., and T. K. LIM
Introduction Perhaps the most striking distinction between asthma and chronic obstructive pulmonary disease (COPD) is that emphysema is not believed to develop with asthma, even when asthma is long-standing and associated with persistent airway obstruction. This conclusion was originally based on postmortem studies (1),but it is broadly supported by tests of lung function, the two best measurements reflecting air-space destruction-the carbon monoxide transfer coefficient (2) and the shape and position of the static expiratory pressure-volume curve of the lungs (3)- both of which show less abnormality in asthma than in many patients with COPD. With this gross difference in the state of the air spaces between COPD and asthma it should be possible to show differences in the interaction between parenchyma and airways in COPD and asthma. In this review, we will first consider work in the 1970s on the static elastic properties of the lungs in asthma and in COPD and how these are related to abnormality of airway function. We will then discuss more recent studies that have examined the relation between the parenchyma and the airways less directly by studying the effects of a deep inflation on airway caliber. Finally, we will comment briefly on other possible interactions. Relation between Static Elastic Properties of the Lungs and Airway Conductance Two abnormalities of the static deflation pressure-volume (P-V) curve of the lungs are thought to distinguish emphysema from airwayobstruction solely caused by intrinsic airway disease: an altered shape of the curve and displacement of the whole P-Vcurve to larger absolute volumes. Studies in the early 1980s showed that the plethysmographic technique may overestimatetrue lung volume in the presence of airway obstruction (4); therefore, much of the earlier literature is difficult to interpret. Nevertheless,it seems likely that displacement of the P-V curve to larger volumes is a much more prominent feature of emphysema than of intrinsic airway disease. Modeling the deflation P-V curve as a single exponential allows a shape factor (k) to be obtained, which is virtually independent of the volume, relative expansion, and maximal distending pressure of the lungs (5), and so is not influenced by artifacts in the plethysmographic method. There seems little doubt that k is higher in emphysema than in asthma (3, 5, 6) (figure 1) although not all studies have shown a clear relation between k and the mor1446
SUMMARY The extent of air-space destruct/on caused by emphysema Is very variable In severe chronic obstructive pulmonary dlaease (COPO), constituting one of the most obvious differences between COPOand asthma. Differences In the static deflation pressure-volume curve between COPO and asthma can easily be shown, but It has been surprisingly difficult to find distinctive mechenlcal features of Impaired airway function caused by air-apace destruction. This may be because in mild airway obstruction related to smoking-particularly In younger subjects-emphysema may be absent, and the predominant site of airway narrowing In the smalleat bronchi and respiratory bronchioles may be the same as that found· In asthma In remission. In more severe obstruction caused by COPO there is almost always very severe Intrinsic disease of the airways and this may so dominate the functional abnormality that It la difficult to detect any additional change because of airspace destruction. Overall, few studies have set out to detect specific effects of parenchymal destruction on airway function. AM REV RESPIR DIS 1991; 143:1446-1449
phologic changes ofemphysema in lungs studied at post-mortem or after surgical removal. Indeed, it has been proposed (7) that changes in the P-V curve in emphysema may not be due directly to gross morphologic changes but to a change in overall lung structure that accompanies (and possibly precedes) the morphologic changes. Similar (but much smaller) changes in the shape of the P-V curve occur with normal aging. Probably some change in the P-V curve occurs with all forms of chronic airway obstruction, including asthma (3, 6). Experimentally small changes in P-V curves have been induced in dogs when airway obstruction was produced by a tracheal valve (8). The idea of a relation between loss of lung recoil pressure and airway obstruction was developed by Dayman (9). Experimental studies in normal subjects in which the normal relationship between airway conductance, lung volume, and lung recoil pressure was disturbed by strapping the chest wall (10), confirmed that in normal lungs lung recoil pressure was a useful indicator of the forces distending the airways during breath holding or breathing at low flows. Subsequently, it was shown that in some patients with COPD and abnormal conductance-volume slopes, the relation between conductance and lung recoil pressure is normal (1l-14). In general, the patients showing a normal conductance-lung recoil relationship have radiologic and other functional evidenceof emphysema and do not have the most severereduction in airway function. In most patients with severeCOPD, however, conductance is reduced at a standard lung recoil pressure. Unfortunately, with the common combination of air space destruction and intrinsic disease of the airways, it is not possible to gauge the respective contributions of loss of airway distension and of intrinsic disease of the airway wall to any narrowing and increase in resistance. Another limitation of this approach is that a normal
relation between conductance and lung recoil pressure does not necessarily imply the total absence of morphologic changes in the airways because the measurement of total airway conductance is relatively insensitive to early changes in peripheral airways. Indeed studies of smokers with few or no respiratory symptoms have shown considerable loss of lung recoil without obvious deterioration in airway function. Clearly, the assumption that the pressure distending intrapulmonary airways can be approximated by static lung recoil pressure is much more precarious in disease when the transduction of forces distending the alveoli to the external airway wall may be altered by breaks in alveolar walls or by uneven distension of the lung. Overall, therefore, it has remained difficult to quantify the role that loss of lung recoil plays in the development of impaired airway function in COPD.
Relative Airway and Parenchymal Hysteresis The effect of a deep inflation on airway function has been extensively studied during the last 30 yr. Early work considered changes in airway function in terms of a change in bronchial muscle activity produced bystretch. Gayrard and colleagues (15)pointed out that the response to a deep inflation in asthma could be airway narrowing rather than the widen-
1 From the Department of Medicine, Respiratory Division, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom, the Department of Internal Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, and the Department of Medicine, National University Hospital, Singapore. 2 Correspondence should be addressed to N. B. Pride, Department of Medicine, Respiratory Division, Royal Postgraduate Medical School, Hammersmith Hospital, London, Wl2 ONN, UK.
1447
INTERACTION BETWEEN PARENCHYMA AND AIRWAYS IN COPD AND ASTHMA
00
_.
~
•
00
.
~_:.;_
• • • • 100
"00
~
00
U '. CI'IIH,o·1
00
_.
~
•~
0
.... ru .......;110 0
,.
..
00
u
eo
•~
r1
02Oll~O·1
llO Otul
1100.1
--------- :--
...... 0.5
2.0
8ronchodilation
1.5
.... o
"§ .~ 1.0 E
.>
0.5
.' j
20
"
t 60
, eo
100
j
120
j
tq e
FEV 1 % pred
Fig. 3. (Top panel) Changes in iJmtilp ratio (mean ± SEM)after bronchoconstric!ion with inhaledhistamine. Closed circles represent the 12 patients with asthma studied byLim and coworkers (18). Open circles represent 24 smokers,and closeddiamonds represent 12exsmokers. (Bottom panel) Changes iniJmtilp ratio(mean ± SEM) after bronchodilation with inhaled betaadrenergicagonists.Opentrianglesrepresent40 neversmokers studied by Fairshter(20); open circles represent 24 smokersand closed diamonds represent 12exsmokers (Lim, Ingram, and Pride, unpublished data). Sixteen subjects with acute asthma studied duringan attack (half-closed circles) and restudied during remission (closed circles) byLim and coworkers(19). Inboth panels dashed and dotted lines represent the regression lineand the 95% confidencelimitscalculatedfrom the results in spontaneous attacks of asthma.
flex being responsible in asthma and COPD for the observed narrowing after DI. Various cycIooxygenaseinhibitor drugs have failed to alter Vm/Vp ratios in normal subjects (20). A recent study in asthma has claimed that a calcium channel blocker attenuates somewhat the narrowing produced by DI (26). These results werethought to support a myogenic response to stretch as a mechanism for airway narrowing after DI. However, postDI values were obtained 30 s after the maneuver, so the true magnitude and time course of the effects of calcium channel blocking drugs are uncertain. Other Interactions On theoretical grounds it would be expected that the size of bronchoconstrictor responses would be highly dependent on mechanics of the airway wall, and the interaction between the parenchyma and the external airway wall (27). The effects might be to alter the submaximal response or to alter the maximal narrowing obtainable. Experimental studies in animals indicate that changing the mechani-
Conclusions There are two interpretations of this difficulty in detecting the effects of abnormal lung parenchyma on airway function. One is that the similarity of airway function in the face of gross differences in the parenchyma explains how the Dutch hypothesis has lasted so long, essentially because intrinsic airway abnormalities and loss of extrinsic airway support give the same end result. The alternative is to conclude that intrinsic airway abnormalities are the predominant abnormality in both asthma and COPD, and the presence of emphysema is of little practical importance in the evolution of airflow obstruction in COPD, merely a late manifestation of age and chronic airway disease, which hardly refutes the Dutch hypothesis. Apart from detecting differences in the P-Vcurve, applied physiologists so far have not been very successful in producing evidence of different mechanisms underlying impaired airway function in asthma and in COPD. New approaches are needed to investigate this problem. References 1. Gough J. Post-mortem differences in "asthma" and chronic bronchitis. Acta Allergol (Kbh) 1961; 16:391-9. 2. Bates DV. Respiratory function in disease. 3rd ed. Philadelphia: WB. Saunders, 1989; 226. 3. Colebatch H1H, Greaves lA, Ng CKY. Pulmonary mechanics in diagnosis. In: deKock MA, Nadel lA, Lewis CM, eds. Mechanisms of airways obstruction in human respiratory disease. Cape Town, South Africa: Balkema, 1979; 25-47. 4. Rodenstein D, Stanescu DC, Francis C. Demonstration of failure of body plethysmography in airway obstruction. 1 Appl Physiol1982; 52:949-54. 5. Gibson Gl, Pride NB, Davis 1, Schroter RC. Exponential description of the static pressurevolume curve of normal and diseased lung. Am Rev Respir Dis 1979; 120:799-811. 6. Petrik-Pereira R, Hunter D, Pride NB. Use of lung pressure-volume curves and helium-sulphur hexafluoride washout to detect emphysema in patients with mild airflow obstruction. ThoraxJ981; 36:29-37. 7. Berend N, Skoog C, Thurlbeck WM. Pressurevolume characteristics of excised human lungs: effects of sex, age and emphysema. 1 Appl Physiol
Introduction Perhaps the most striking distinction between asthma and chronic obstructive pulmonary disease (COPD) is that emphysema is not believed to develop with asthma, even when asthma is long-standing and associated with persistent airway obstruction. This conclusion was originally based on postmortem studies (1),but it is broadly supported by tests of lung function, the two best measurements reflecting air-space destruction-the carbon monoxide transfer coefficient (2) and the shape and position of the static expiratory pressure-volume curve of the lungs (3)- both of which show less abnormality in asthma than in many patients with COPD. With this gross difference in the state of the air spaces between COPD and asthma it should be possible to show differences in the interaction between parenchyma and airways in COPD and asthma. In this review, we will first consider work in the 1970s on the static elastic properties of the lungs in asthma and in COPD and how these are related to abnormality of airway function. We will then discuss more recent studies that have examined the relation between the parenchyma and the airways less directly by studying the effects of a deep inflation on airway caliber. Finally, we will comment briefly on other possible interactions. Relation between Static Elastic Properties of the Lungs and Airway Conductance Two abnormalities of the static deflation pressure-volume (P-V) curve of the lungs are thought to distinguish emphysema from airwayobstruction solely caused by intrinsic airway disease: an altered shape of the curve and displacement of the whole P-Vcurve to larger absolute volumes. Studies in the early 1980s showed that the plethysmographic technique may overestimatetrue lung volume in the presence of airway obstruction (4); therefore, much of the earlier literature is difficult to interpret. Nevertheless,it seems likely that displacement of the P-V curve to larger volumes is a much more prominent feature of emphysema than of intrinsic airway disease. Modeling the deflation P-V curve as a single exponential allows a shape factor (k) to be obtained, which is virtually independent of the volume, relative expansion, and maximal distending pressure of the lungs (5), and so is not influenced by artifacts in the plethysmographic method. There seems little doubt that k is higher in emphysema than in asthma (3, 5, 6) (figure 1) although not all studies have shown a clear relation between k and the mor1446
SUMMARY The extent of air-space destruct/on caused by emphysema Is very variable In severe chronic obstructive pulmonary dlaease (COPO), constituting one of the most obvious differences between COPOand asthma. Differences In the static deflation pressure-volume curve between COPO and asthma can easily be shown, but It has been surprisingly difficult to find distinctive mechenlcal features of Impaired airway function caused by air-apace destruction. This may be because in mild airway obstruction related to smoking-particularly In younger subjects-emphysema may be absent, and the predominant site of airway narrowing In the smalleat bronchi and respiratory bronchioles may be the same as that found· In asthma In remission. In more severe obstruction caused by COPO there is almost always very severe Intrinsic disease of the airways and this may so dominate the functional abnormality that It la difficult to detect any additional change because of airspace destruction. Overall, few studies have set out to detect specific effects of parenchymal destruction on airway function. AM REV RESPIR DIS 1991; 143:1446-1449
phologic changes ofemphysema in lungs studied at post-mortem or after surgical removal. Indeed, it has been proposed (7) that changes in the P-V curve in emphysema may not be due directly to gross morphologic changes but to a change in overall lung structure that accompanies (and possibly precedes) the morphologic changes. Similar (but much smaller) changes in the shape of the P-V curve occur with normal aging. Probably some change in the P-V curve occurs with all forms of chronic airway obstruction, including asthma (3, 6). Experimentally small changes in P-V curves have been induced in dogs when airway obstruction was produced by a tracheal valve (8). The idea of a relation between loss of lung recoil pressure and airway obstruction was developed by Dayman (9). Experimental studies in normal subjects in which the normal relationship between airway conductance, lung volume, and lung recoil pressure was disturbed by strapping the chest wall (10), confirmed that in normal lungs lung recoil pressure was a useful indicator of the forces distending the airways during breath holding or breathing at low flows. Subsequently, it was shown that in some patients with COPD and abnormal conductance-volume slopes, the relation between conductance and lung recoil pressure is normal (1l-14). In general, the patients showing a normal conductance-lung recoil relationship have radiologic and other functional evidenceof emphysema and do not have the most severereduction in airway function. In most patients with severeCOPD, however, conductance is reduced at a standard lung recoil pressure. Unfortunately, with the common combination of air space destruction and intrinsic disease of the airways, it is not possible to gauge the respective contributions of loss of airway distension and of intrinsic disease of the airway wall to any narrowing and increase in resistance. Another limitation of this approach is that a normal
relation between conductance and lung recoil pressure does not necessarily imply the total absence of morphologic changes in the airways because the measurement of total airway conductance is relatively insensitive to early changes in peripheral airways. Indeed studies of smokers with few or no respiratory symptoms have shown considerable loss of lung recoil without obvious deterioration in airway function. Clearly, the assumption that the pressure distending intrapulmonary airways can be approximated by static lung recoil pressure is much more precarious in disease when the transduction of forces distending the alveoli to the external airway wall may be altered by breaks in alveolar walls or by uneven distension of the lung. Overall, therefore, it has remained difficult to quantify the role that loss of lung recoil plays in the development of impaired airway function in COPD.
Relative Airway and Parenchymal Hysteresis The effect of a deep inflation on airway function has been extensively studied during the last 30 yr. Early work considered changes in airway function in terms of a change in bronchial muscle activity produced bystretch. Gayrard and colleagues (15)pointed out that the response to a deep inflation in asthma could be airway narrowing rather than the widen-
1 From the Department of Medicine, Respiratory Division, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom, the Department of Internal Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, and the Department of Medicine, National University Hospital, Singapore. 2 Correspondence should be addressed to N. B. Pride, Department of Medicine, Respiratory Division, Royal Postgraduate Medical School, Hammersmith Hospital, London, Wl2 ONN, UK.
1447
INTERACTION BETWEEN PARENCHYMA AND AIRWAYS IN COPD AND ASTHMA
00
_.
~
•
00
.
~_:.;_
• • • • 100
"00
~
00
U '. CI'IIH,o·1
00
_.
~
•~
0
.... ru .......;110 0
,.
..
00
u
eo
•~
r1
02Oll~O·1
llO Otul
1100.1
--------- :--
...... 0.5
2.0
8ronchodilation
1.5
.... o
"§ .~ 1.0 E
.>
0.5
.' j
20
"
t 60
, eo
100
j
120
j
tq e
FEV 1 % pred
Fig. 3. (Top panel) Changes in iJmtilp ratio (mean ± SEM)after bronchoconstric!ion with inhaledhistamine. Closed circles represent the 12 patients with asthma studied byLim and coworkers (18). Open circles represent 24 smokers,and closeddiamonds represent 12exsmokers. (Bottom panel) Changes iniJmtilp ratio(mean ± SEM) after bronchodilation with inhaled betaadrenergicagonists.Opentrianglesrepresent40 neversmokers studied by Fairshter(20); open circles represent 24 smokersand closed diamonds represent 12exsmokers (Lim, Ingram, and Pride, unpublished data). Sixteen subjects with acute asthma studied duringan attack (half-closed circles) and restudied during remission (closed circles) byLim and coworkers(19). Inboth panels dashed and dotted lines represent the regression lineand the 95% confidencelimitscalculatedfrom the results in spontaneous attacks of asthma.
flex being responsible in asthma and COPD for the observed narrowing after DI. Various cycIooxygenaseinhibitor drugs have failed to alter Vm/Vp ratios in normal subjects (20). A recent study in asthma has claimed that a calcium channel blocker attenuates somewhat the narrowing produced by DI (26). These results werethought to support a myogenic response to stretch as a mechanism for airway narrowing after DI. However, postDI values were obtained 30 s after the maneuver, so the true magnitude and time course of the effects of calcium channel blocking drugs are uncertain. Other Interactions On theoretical grounds it would be expected that the size of bronchoconstrictor responses would be highly dependent on mechanics of the airway wall, and the interaction between the parenchyma and the external airway wall (27). The effects might be to alter the submaximal response or to alter the maximal narrowing obtainable. Experimental studies in animals indicate that changing the mechani-
Conclusions There are two interpretations of this difficulty in detecting the effects of abnormal lung parenchyma on airway function. One is that the similarity of airway function in the face of gross differences in the parenchyma explains how the Dutch hypothesis has lasted so long, essentially because intrinsic airway abnormalities and loss of extrinsic airway support give the same end result. The alternative is to conclude that intrinsic airway abnormalities are the predominant abnormality in both asthma and COPD, and the presence of emphysema is of little practical importance in the evolution of airflow obstruction in COPD, merely a late manifestation of age and chronic airway disease, which hardly refutes the Dutch hypothesis. Apart from detecting differences in the P-Vcurve, applied physiologists so far have not been very successful in producing evidence of different mechanisms underlying impaired airway function in asthma and in COPD. New approaches are needed to investigate this problem. References 1. Gough J. Post-mortem differences in "asthma" and chronic bronchitis. Acta Allergol (Kbh) 1961; 16:391-9. 2. Bates DV. Respiratory function in disease. 3rd ed. Philadelphia: WB. Saunders, 1989; 226. 3. Colebatch H1H, Greaves lA, Ng CKY. Pulmonary mechanics in diagnosis. In: deKock MA, Nadel lA, Lewis CM, eds. Mechanisms of airways obstruction in human respiratory disease. Cape Town, South Africa: Balkema, 1979; 25-47. 4. Rodenstein D, Stanescu DC, Francis C. Demonstration of failure of body plethysmography in airway obstruction. 1 Appl Physiol1982; 52:949-54. 5. Gibson Gl, Pride NB, Davis 1, Schroter RC. Exponential description of the static pressurevolume curve of normal and diseased lung. Am Rev Respir Dis 1979; 120:799-811. 6. Petrik-Pereira R, Hunter D, Pride NB. Use of lung pressure-volume curves and helium-sulphur hexafluoride washout to detect emphysema in patients with mild airflow obstruction. ThoraxJ981; 36:29-37. 7. Berend N, Skoog C, Thurlbeck WM. Pressurevolume characteristics of excised human lungs: effects of sex, age and emphysema. 1 Appl Physiol
