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Varieties of airway narrowing in severe and fatal asthma
Varieties of airway fatal asthma James
narrowing
C. Hogg, M.D. Vancouver, British Columbia, Canada
The sequential events that cause the airways to narrow have recently been reviewed by Moreno et al.’ and are summarized in Fig. I. The first step in airways narrowing is the activation of airways smooth muscle, followed by smooth muscle contraction and shortening, which reduce the airways lumen and increase airways resistance. The purpose of this article is to summarize these events, emphasizing those most likely to be important as a cause of death in asthma. SMOOTH
in severe and
MUSCLE
hkuction]
ACTIVATION
In a recent review of the neural control of the airways, Barnes’ evaluated the growing literature on the activation of smooth muscle by mediators. The excess airways narrowing seen in asthma could result from the muscle having too few P-adrenergic receptors, which relax smooth muscle, or from too many receptors for mediators that contract it. There appears, however, to be little direct evidence to support either of these hypotheses. It is now known that the P-adrenergic receptors are widely distributed in lung tissue and that P-adrenergic agonists can affect the airway lumen by increasing airways secretion as well as smooth muscle contraction. It is also possible that enhanced reactivity to a mediator can be brought about by the unmasking of receptors for this mediator by treatment with another drug. Agonists can also activate airway smooth muscle if their local concentration increases so that a greater number of their receptors is occupied. The local concentration of mediators can be increased by changes in either epithelial or vascular permeability and in situations in which bronchial blood flow is decreased, so that locally generated mediators are not removed. In this situation the muscle is activated because of increased receptor occupancy rather than an abnormal receptor density. Again, there is little direct evidence
From the Department of Pathology, University of British Columbia, and the Pulmonary Research Laboratory, St. Paul’s Hospital. Vancouver. British Columbia, Canada. Reprint requests: James C. Hogg, M.D., Pulmonary Research Laboratory, St. Paul’s Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
FIG. 1. Steps involved in airway narrowing in which airway resistance is a function of muscle activation, shortening, and wall thickness (including secretion into the lumen). Death in asthma is frequently associated with increased wall thickness and plugging of the lumen, but may occur in some cases from muscle shortening. ASM, airway smooth muscle; Raw, resistance of the airways. (Reproduced with permission from Moreno RH, Hogg JC, Pare PD. Am Rev Respir Dis 1986;133:1171-80.)
in support of this hypothesis as a cause of death in asthma. SMOOTH MUSCLE SHORTENING Several studies3-’ have reported an increased amount of muscle in the airways of patients with asthma, with the greatest increase in medium-sized airways. This is thought to be an absolute increase in the amount of muscle rather than an apparent increase due to bronchoconstriction, and has been attributed to muscle hyperplasia rather than to hypertrophy.6 Although there have been a substantial number7-“’ of in vitro studies of muscle contraction in strips of airways prepared from human bronchi, very few of these studies have been performed on airways from patients with asthma.“. ‘* Although there is some evidence for increased maximum contraction,‘* this finding could be 417
418 Hogg
.I ALLERGY
CLIN. IMMUNOL SEPTEMBER 1987
severe airways obstruction and no mucus plugging or submucosal edema of the airways is found postmortem. Whether death can occur because of ii L+lange in the loading of the muscle is an unanswered yucs(ion. WALL THICKNESS
LH4lGTH FIG. 2. Length-tension relationship of airway smooth muscle. Contraction can produce a variety of changes ranging from an increased tension without shortening (A), which will not affect the airway lumen, to maximum shortening with no change in tension (8). which will have the greatest effect on the lumen and produce the maximum change
in airwav resistance.
consistent with an increased amount of airways muscle rather than abnormal muscle function. Fig. 2 shows the length-tension relationship for smooth muscle, which defines the conditions under which shortening occurs. If the muscle contracts against a preload, it must first generate enough force to move the load before it can shorten (A). Conversely, when no preJaad is placed on the muscle, it can shorten to 20% to 30% of its resting length (B). In situation A there will be no airways narrowing and therefore no change in resistance, whereas in situation B the airways will narrow maximally and resistance can increase up to 600-fold in airways in which the muscle completely encircles the lumen. Recent studies of the tracheal3 show that the cartilage provides a preload that prevents muscle shortening, and it seems likely that this is also true of the cartilage in the main stem and intrapulmonary bronchi. The lung parenchyma places a preload on the muscle in the intrapulmonary airways that is increased by lung expansion. When these preloads are reduced by either softening the airways cartilageI or breathing at low lung volume,” there is a substantial increase in airways responsiveness. Thus it is possible to increase airway narrowing by altering the loads placed upon the muscle without necessarily changing the intrinsic properties of the muscle itself. It seems very likely that excess muscle shortening is the cause of death in some casesof asthma. This is likely to be true when paknts with asthma die of
AN0 SECRETIONS
The airway may also be induced to narrow by an exudation onto the surface of the airways 11~rnen. Thr: surface of the normal peripheral airway5 is known to be covered by surfactant. which has a low surface tension. ” When surfactant is replaced by an inflammatoty exudate, the increased surface tension can be expected to narrow the airway limen. An increase in the luminal contents because of further exudation into the airways surface will enhance the lumen narrowing. in patients who die of status asthmaticus the airways are frequently filled with tenacious. viscid plugs.“. ” These plugs are most apparent in the segmental and subsegmental airways, but can extend all the way to the respiratory bronchioles.” They are formed from an exudate containing plasma proteins. intlammatory cells, sloughed epithelium, and mucus. They can be extremely tenacious and sometimes form casts of the airways that are coughed up and appear in sputum as the so-called Curschman spirals.‘” The sputum also contains large numbers of inflammatory cells with many eosinophils, and granules from the eosinophils sometimes form elongated crystalline structures called Charcot-Leyden crystals.“’ Compact clusters of airway cpithelial cells named Creola bodies’! can also be demonstrated in the airways secretions of patients with asthma. When severe asthma has been present. the airway epithelium and submucosa are grossly abnormal. In some areas the basement membrane is bare due to the epithelial sloughing, and in other areas the repair process results in a covering of either goblet or squamous cells rather than the normal pseudostratified respiratory epithelium. The basement membrane of the epithelium is thickened“‘. ” due to collagen deposition and increased deposition of immunoglobulins rather than to true thickening of the basal lamina.” The tracheobronchial mucous glands are increased in size! and the submucosa is increased in amount because of edema and infiltration with migrating inHammatory cells, particularly the eosinophil? “. ik The tissue swelling produced by the exudation ol fluid and cells, vascular congestion, and the hypcr-
trophy of muscle and glands are all of a liquid nature and therefore incompressible. Thus even if the smooth muscle shortens by a normal amount, the thickened mucosa will amplify the effect that the muscle contraction has on the lumen.” Moreno et al.’ calculated that small amounts of wall thickening can amplify the
VOLUME NUMBER
80 3. PART 2
Airway
increase in resistance produced by normal smooth muscle contraction by an order of magnitude. Thus the problem in most cases of severe and fatal asthma may be the excessive inflammatory process in the submucosa and lumen of the airways that results in severe airways narrowing when coupled with either normal or excessive smooth muscle contraction. REFERENCES
12.
13.
I. Moreno RH, Hogg JC, Pare PD. Mechanisms of airway narrowing. Am Rev Respir Dis 1986;133:1171-80. 2. Barnes PJ. Neurocontrol of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-1314. 3. Dunnill MS, Massarella GR. Anderson IA. A comparison of the quantitative anatomy of the bronchi in normal subjects. in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969;24: 176-9. 4. Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med 1922;30:689. 5. Sobonya RE. Concise clinical study. Quantitative structural alterations in .Inng-standing allergic asthma. Am Rev Respir Dis 1984;130:289. 6. Heard BE, Hossdin S. Hyperplasia of bronchial muscle in asthma. J Path01 1973;110:319. 7. Armour CL, Lazar NM, Schellenberg RR, et al. A comparison of in vivo and in vitro human airway reactivity to histamine. Am Rev Respir Dis 1984;129:907-10. 8. Vincent JS, Black JL, Yan K, Armour CL, Donnelly PD, Woolcock AJ. A comparison of in vivo and in vitro responses to histamine in human airways. Am Rev Respir Dis 1983; 12X:X75-9. 9. Taylor SM. Pare PD. Armour CL, Hogg JC, Schellenberg RR. Airway reactivity in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:32-5. 10. Adams OK, Lichtenstein LM. In vitro studies of antigen-
Cardiac pathology Frederick
11.
J. Schoen,
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
narrowing
in severe
and fatal
asthma
induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol 1979;122:555-62. Patterson JW, Lulich KL, Goldie RG. The role of beta adrenergic receptors in bronchial hyperreactivity. In: Morley I, ed. Bronchial hyperreactivity. London: Academic Press. 1982: 19-39. Schellenberg RR. Foster A. In vitro response of human asthmatic airway and pulmonary vascular smooth muscle. Int Arch Allergy Appl lmmunol 1984:75:237-41. James AL. Pare PD. Moreno R, Hogg JC. Smooth muscle shortening and airway narrowing in porcine tracheal ring. Am Rev Respir Dis 1986; 133: I I3A. Moreno RH, Dahlby R, Hogg JC, Pare PD. Increased airway responsiveness caused by airway cartilage softening in rabbits. Am Rev Respir Dis 1985;13lA:288. Martin JG, Dong-Jie D, Macklem PT. Effective lung volume on methacholine-induced bronchoconstriction in normal subjects. Am Rev Respir Dis 1986;133:15A. Macklem PT. Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8:191-203. Dunnill MS. The pathology of asthma, with special reference to the changes in the bronchial mucosa. J Clin Path01 1960;13:27-33. Dunnill MS. The pathology of asthma. In: Porter R, Birch J, eds. Identification of asthma. Ciba Foundation Symposium Study Group No. 38. Edinburgh, London: Churchill Livingstone Inc. 1971:35-46. Riglcr L. Bronchial asthma. Am J Roentgen01 1938;39:353. Sanerkin NG, Evans DMD. The sputum in bronchial asthma: pathopneumonic patterns. J Pathol Bacterial 1965;89:535-41. Naylor B. The shedding of the mucosa of rhe bronchial tree in man. Thorax 1962:17:69. McCarter JH: Vazquez JJ. The bronchial basement membrane in asthma. Arch Path01 1966;82:328. Freedman BJ. Functional geometry of the bronchi. Bull Physiol Pathol Respir 1972;85:45-5 I.
in asthma
M.D., Ph.D. Boston, Mass.
Asthma-related death is relatively uncommon, but cardiac changes could be contributory in some cases. Severe alterations of cardiopulmonary physiology occur during acute asthmatic attacks.’ However, unexpected death is not always related to an acute prolonged episode’ and may occur despite and during From the Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Frederick J. Schoen, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115.
apparent recovery from an acute attack.3,4 Unexpected death is often sudden, suggesting arrhythmia as a mechanism. However, whether and to what degree cardiac morphologic changes are associated (and potentially contributory) have not been adequately studied. Injury could be either acute or the cumulative effect of multiple recent or old episodes. Furthermore, the bronchodilators used in asthma treatment may cause adverse reactions. P-Adrenergic agonists both alone’ and in concert with methylxanthines6 have been implicated. Nevertheless, despite tie potential importance of cardiac effects of asthma and its treatment, 419
narrowing
C. Hogg, M.D. Vancouver, British Columbia, Canada
The sequential events that cause the airways to narrow have recently been reviewed by Moreno et al.’ and are summarized in Fig. I. The first step in airways narrowing is the activation of airways smooth muscle, followed by smooth muscle contraction and shortening, which reduce the airways lumen and increase airways resistance. The purpose of this article is to summarize these events, emphasizing those most likely to be important as a cause of death in asthma. SMOOTH
in severe and
MUSCLE
hkuction]
ACTIVATION
In a recent review of the neural control of the airways, Barnes’ evaluated the growing literature on the activation of smooth muscle by mediators. The excess airways narrowing seen in asthma could result from the muscle having too few P-adrenergic receptors, which relax smooth muscle, or from too many receptors for mediators that contract it. There appears, however, to be little direct evidence to support either of these hypotheses. It is now known that the P-adrenergic receptors are widely distributed in lung tissue and that P-adrenergic agonists can affect the airway lumen by increasing airways secretion as well as smooth muscle contraction. It is also possible that enhanced reactivity to a mediator can be brought about by the unmasking of receptors for this mediator by treatment with another drug. Agonists can also activate airway smooth muscle if their local concentration increases so that a greater number of their receptors is occupied. The local concentration of mediators can be increased by changes in either epithelial or vascular permeability and in situations in which bronchial blood flow is decreased, so that locally generated mediators are not removed. In this situation the muscle is activated because of increased receptor occupancy rather than an abnormal receptor density. Again, there is little direct evidence
From the Department of Pathology, University of British Columbia, and the Pulmonary Research Laboratory, St. Paul’s Hospital. Vancouver. British Columbia, Canada. Reprint requests: James C. Hogg, M.D., Pulmonary Research Laboratory, St. Paul’s Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
FIG. 1. Steps involved in airway narrowing in which airway resistance is a function of muscle activation, shortening, and wall thickness (including secretion into the lumen). Death in asthma is frequently associated with increased wall thickness and plugging of the lumen, but may occur in some cases from muscle shortening. ASM, airway smooth muscle; Raw, resistance of the airways. (Reproduced with permission from Moreno RH, Hogg JC, Pare PD. Am Rev Respir Dis 1986;133:1171-80.)
in support of this hypothesis as a cause of death in asthma. SMOOTH MUSCLE SHORTENING Several studies3-’ have reported an increased amount of muscle in the airways of patients with asthma, with the greatest increase in medium-sized airways. This is thought to be an absolute increase in the amount of muscle rather than an apparent increase due to bronchoconstriction, and has been attributed to muscle hyperplasia rather than to hypertrophy.6 Although there have been a substantial number7-“’ of in vitro studies of muscle contraction in strips of airways prepared from human bronchi, very few of these studies have been performed on airways from patients with asthma.“. ‘* Although there is some evidence for increased maximum contraction,‘* this finding could be 417
418 Hogg
.I ALLERGY
CLIN. IMMUNOL SEPTEMBER 1987
severe airways obstruction and no mucus plugging or submucosal edema of the airways is found postmortem. Whether death can occur because of ii L+lange in the loading of the muscle is an unanswered yucs(ion. WALL THICKNESS
LH4lGTH FIG. 2. Length-tension relationship of airway smooth muscle. Contraction can produce a variety of changes ranging from an increased tension without shortening (A), which will not affect the airway lumen, to maximum shortening with no change in tension (8). which will have the greatest effect on the lumen and produce the maximum change
in airwav resistance.
consistent with an increased amount of airways muscle rather than abnormal muscle function. Fig. 2 shows the length-tension relationship for smooth muscle, which defines the conditions under which shortening occurs. If the muscle contracts against a preload, it must first generate enough force to move the load before it can shorten (A). Conversely, when no preJaad is placed on the muscle, it can shorten to 20% to 30% of its resting length (B). In situation A there will be no airways narrowing and therefore no change in resistance, whereas in situation B the airways will narrow maximally and resistance can increase up to 600-fold in airways in which the muscle completely encircles the lumen. Recent studies of the tracheal3 show that the cartilage provides a preload that prevents muscle shortening, and it seems likely that this is also true of the cartilage in the main stem and intrapulmonary bronchi. The lung parenchyma places a preload on the muscle in the intrapulmonary airways that is increased by lung expansion. When these preloads are reduced by either softening the airways cartilageI or breathing at low lung volume,” there is a substantial increase in airways responsiveness. Thus it is possible to increase airway narrowing by altering the loads placed upon the muscle without necessarily changing the intrinsic properties of the muscle itself. It seems very likely that excess muscle shortening is the cause of death in some casesof asthma. This is likely to be true when paknts with asthma die of
AN0 SECRETIONS
The airway may also be induced to narrow by an exudation onto the surface of the airways 11~rnen. Thr: surface of the normal peripheral airway5 is known to be covered by surfactant. which has a low surface tension. ” When surfactant is replaced by an inflammatoty exudate, the increased surface tension can be expected to narrow the airway limen. An increase in the luminal contents because of further exudation into the airways surface will enhance the lumen narrowing. in patients who die of status asthmaticus the airways are frequently filled with tenacious. viscid plugs.“. ” These plugs are most apparent in the segmental and subsegmental airways, but can extend all the way to the respiratory bronchioles.” They are formed from an exudate containing plasma proteins. intlammatory cells, sloughed epithelium, and mucus. They can be extremely tenacious and sometimes form casts of the airways that are coughed up and appear in sputum as the so-called Curschman spirals.‘” The sputum also contains large numbers of inflammatory cells with many eosinophils, and granules from the eosinophils sometimes form elongated crystalline structures called Charcot-Leyden crystals.“’ Compact clusters of airway cpithelial cells named Creola bodies’! can also be demonstrated in the airways secretions of patients with asthma. When severe asthma has been present. the airway epithelium and submucosa are grossly abnormal. In some areas the basement membrane is bare due to the epithelial sloughing, and in other areas the repair process results in a covering of either goblet or squamous cells rather than the normal pseudostratified respiratory epithelium. The basement membrane of the epithelium is thickened“‘. ” due to collagen deposition and increased deposition of immunoglobulins rather than to true thickening of the basal lamina.” The tracheobronchial mucous glands are increased in size! and the submucosa is increased in amount because of edema and infiltration with migrating inHammatory cells, particularly the eosinophil? “. ik The tissue swelling produced by the exudation ol fluid and cells, vascular congestion, and the hypcr-
trophy of muscle and glands are all of a liquid nature and therefore incompressible. Thus even if the smooth muscle shortens by a normal amount, the thickened mucosa will amplify the effect that the muscle contraction has on the lumen.” Moreno et al.’ calculated that small amounts of wall thickening can amplify the
VOLUME NUMBER
80 3. PART 2
Airway
increase in resistance produced by normal smooth muscle contraction by an order of magnitude. Thus the problem in most cases of severe and fatal asthma may be the excessive inflammatory process in the submucosa and lumen of the airways that results in severe airways narrowing when coupled with either normal or excessive smooth muscle contraction. REFERENCES
12.
13.
I. Moreno RH, Hogg JC, Pare PD. Mechanisms of airway narrowing. Am Rev Respir Dis 1986;133:1171-80. 2. Barnes PJ. Neurocontrol of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-1314. 3. Dunnill MS, Massarella GR. Anderson IA. A comparison of the quantitative anatomy of the bronchi in normal subjects. in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969;24: 176-9. 4. Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med 1922;30:689. 5. Sobonya RE. Concise clinical study. Quantitative structural alterations in .Inng-standing allergic asthma. Am Rev Respir Dis 1984;130:289. 6. Heard BE, Hossdin S. Hyperplasia of bronchial muscle in asthma. J Path01 1973;110:319. 7. Armour CL, Lazar NM, Schellenberg RR, et al. A comparison of in vivo and in vitro human airway reactivity to histamine. Am Rev Respir Dis 1984;129:907-10. 8. Vincent JS, Black JL, Yan K, Armour CL, Donnelly PD, Woolcock AJ. A comparison of in vivo and in vitro responses to histamine in human airways. Am Rev Respir Dis 1983; 12X:X75-9. 9. Taylor SM. Pare PD. Armour CL, Hogg JC, Schellenberg RR. Airway reactivity in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:32-5. 10. Adams OK, Lichtenstein LM. In vitro studies of antigen-
Cardiac pathology Frederick
11.
J. Schoen,
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
narrowing
in severe
and fatal
asthma
induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol 1979;122:555-62. Patterson JW, Lulich KL, Goldie RG. The role of beta adrenergic receptors in bronchial hyperreactivity. In: Morley I, ed. Bronchial hyperreactivity. London: Academic Press. 1982: 19-39. Schellenberg RR. Foster A. In vitro response of human asthmatic airway and pulmonary vascular smooth muscle. Int Arch Allergy Appl lmmunol 1984:75:237-41. James AL. Pare PD. Moreno R, Hogg JC. Smooth muscle shortening and airway narrowing in porcine tracheal ring. Am Rev Respir Dis 1986; 133: I I3A. Moreno RH, Dahlby R, Hogg JC, Pare PD. Increased airway responsiveness caused by airway cartilage softening in rabbits. Am Rev Respir Dis 1985;13lA:288. Martin JG, Dong-Jie D, Macklem PT. Effective lung volume on methacholine-induced bronchoconstriction in normal subjects. Am Rev Respir Dis 1986;133:15A. Macklem PT. Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8:191-203. Dunnill MS. The pathology of asthma, with special reference to the changes in the bronchial mucosa. J Clin Path01 1960;13:27-33. Dunnill MS. The pathology of asthma. In: Porter R, Birch J, eds. Identification of asthma. Ciba Foundation Symposium Study Group No. 38. Edinburgh, London: Churchill Livingstone Inc. 1971:35-46. Riglcr L. Bronchial asthma. Am J Roentgen01 1938;39:353. Sanerkin NG, Evans DMD. The sputum in bronchial asthma: pathopneumonic patterns. J Pathol Bacterial 1965;89:535-41. Naylor B. The shedding of the mucosa of rhe bronchial tree in man. Thorax 1962:17:69. McCarter JH: Vazquez JJ. The bronchial basement membrane in asthma. Arch Path01 1966;82:328. Freedman BJ. Functional geometry of the bronchi. Bull Physiol Pathol Respir 1972;85:45-5 I.
in asthma
M.D., Ph.D. Boston, Mass.
Asthma-related death is relatively uncommon, but cardiac changes could be contributory in some cases. Severe alterations of cardiopulmonary physiology occur during acute asthmatic attacks.’ However, unexpected death is not always related to an acute prolonged episode’ and may occur despite and during From the Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Frederick J. Schoen, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115.
apparent recovery from an acute attack.3,4 Unexpected death is often sudden, suggesting arrhythmia as a mechanism. However, whether and to what degree cardiac morphologic changes are associated (and potentially contributory) have not been adequately studied. Injury could be either acute or the cumulative effect of multiple recent or old episodes. Furthermore, the bronchodilators used in asthma treatment may cause adverse reactions. P-Adrenergic agonists both alone’ and in concert with methylxanthines6 have been implicated. Nevertheless, despite tie potential importance of cardiac effects of asthma and its treatment, 419