- Email: [email protected]
Airway Hyperresponsiveness
Table 1—Neutrophil Inflammation 8 h After the Allergen Challenge Is Allergen Specific Variables Not sensitized/OVA challenged OVA sensitized/ OVA challenged OVA sensitized/RW challenged Not sensitized/RW challenged RW sensitized/RW challenged RW sensitized/OVA challenged
Total Cell Count, Macrophages, Neutrophils, ⫻ 103 cells ⫻ 103 cells ⫻ 103 cells 43
27
16
167*
12
155*
41
28
14
38
25
12
131*
31
101*
41
26
16
*p ⬍ 0.05 compared to not sensitized/OVA challenged, OVA sensitized/RW challenged, not sensitized/RW challenged, and RW sensitized/OVA challenged.
Taken together, these results demonstrate that neutrophil influx after allergen challenge requires prior sensitization and is allergen-specific. Furthermore, we demonstrated that this transient neutrophil inflammation is mediated through the Fc␥ receptor (but not the Fc⑀RI) and is dependent on the presence of the antibody. The contribution of this early and transient neutrophil phase to the development of subsequent eosinophil and lymphocyte accumulation and to altered airway function events remains to be determined.
References 1 Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001; 344:350 –362 2 Wenzel SE, Szefler SJ, Leung DY, et al. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997; 156:737–743 3 Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991; 143:351–357 4 Tanizaki Y, Kitani H, Okazaki M, et al. Effects of long-term glucocorticoid therapy on bronchoalveolar cells in adult patients with bronchial asthma. J Asthma 1993; 30:309 –318 5 Fahy JV, Kim KW, Liu J, et al. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95:843– 852 6 Koh YY, Dupuid R, Pollice M, et al. Neutrophils recruited to the lungs of humans by segmental allergen challenge display a reduced chemotactic response to leukotriene B4. Am J Respir Cell Mol Biol 1993; 8:493– 499 7 Kelly EA, Busse WW, Jarjour NN. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med 2000; 162:1157–1161 8 Nocker RE, Out TA, Weller FR, et al. Influx of neutrophils into the airway lumen at 4 h after segmental allergen challenge in asthma. Int Arch Allergy Immunol 1999; 119: 45–53 9 Tomkinson A, Cieslewicz G, Duez C, et al. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. Am J Respir Crit Care Med 2001; 163:721–730 www.chestjournal.org
Airway Hyperresponsiveness* Paul M. O’Byrne, MB, FCCP; and Mark D. Inman, MD
Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Measurements of airway responsiveness are useful in making a diagnosis of asthma, particularly in patients who have symptoms that are consistent with asthma and who have no evidence of airflow obstruction. These tests can be performed quickly, safely, and reproducibly. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness. These changes in airway hyperresponsiveness are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects. They are, however, similar to changes occurring in asthmatic patients that are associated with worsening asthma control. The mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to fully explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients. (CHEST 2003; 123:411S– 416S) Abbreviation: PC20 ⫽ provocative concentration of a substance causing a 20% fall in FEV1
responsiveness is a term that describes the A irway ability of the airways to narrow after exposure to
constrictor agonists. Thus, airway hyperresponsiveness is an increased ability to develop this response. Airway hyperresponsiveness consists of an increased sensitivity of the airways to constrictor agonists, as indicated by a smaller concentration of a constrictor agonist needed to initiate the bronchoconstrictor response, a steeper slope of the dose-response, and a greater maximal response to the agonist (Fig 1).1 Airway responsiveness is measured using inhalation challenges with airway constrictor agonists, such as histamine or methacholine, in both clinical and research laboratories. This is because airway hyperresponsiveness has been identified as an important feature in patients with current, symptomatic asthma and, indeed, has been included in the defining characteristics of asthma.2 In addition, the severity of airway hyperresponsiveness cor-
*From the Firestone Institute for Respiratory Health, St. Joseph’s Hospital, Hamilton, ON, Canada. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Paul M. O’Byrne, MB, FCCP, Firestone Institute for Respiratory Health, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON, L8N 4A6 Canada; e-mail: obyrnep@ mcmaster.ca CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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Figure 1. The change in FEV1 vs baseline, induced by increasing doses of a bronchoconstrictor stimulus (methacholine) in patients with mild, moderate and severe asthma vs healthy individuals. The PC20 value is calculated by interpolating a 20% fall in FEV1 to the log-linear dose-response curve for each individual. Asthmatic subjects have a reduced threshold response (a), indicating increased sensitivity of the airways, an increased slope (b), indicating increased reactivity of the airways, and an increased maximal response (c).
relates with the severity of asthma3 and with the amount of treatment needed to control symptoms.4 The methods for measuring airway responsiveness have been standardized4 and are widely accepted.
Historical Perspective The initial observation that bronchoconstriction occurs more readily in asthmatic patients when compared to non-asthmatic patients after exposure to a constrictor agonist was made in 1921 by Alexander and Paddock,5 who demonstrated “asthmatic breathing” in asthmatic subjects, but not in healthy subjects, after subcutaneous administration of the cholinergic agonist pilocarpine. This observation was confirmed by Weiss et al6 in 1932, who reported that asthmatic subjects, but not healthy subjects, developed bronchoconstriction, as measured by changes in the vital capacity, after being given IV histamine. Tiffeneau and Beauvallet7 were the first to describe the use of acetylcholine inhalation tests to determine the degree of airway responsiveness in asthmatic patients, while Curry8 identified the fact that bronchoconstriction developed in asthmatic subjects after histamine was given intramuscularly, IV, or by nebulization.
Direct-Acting and Indirect-Acting Stimuli It is now known that airway hyperresponsiveness is present in asthmatic subjects to many chemical or physical stimuli other than inhaled histamine or the cholinergic 412S
agonists. These include chemical mediators such as cysteinyl leukotrienes C4 and D49 prostaglandin D210 and F2.11 All of these agonists cause bronchoconstriction by stimulating receptors that are present on airway smooth muscle. They are, therefore, considered to be directacting measures of airway responsiveness. An important distinction needs to be made between these methods of measuring airway responsiveness and indirect methods. Indirect-acting stimuli are those that cause bronchoconstriction in asthmatic patients by releasing constrictor mediators from cells in the airways. These stimuli include adenosine,12 exercise,13 hyperventilation of cold, dry air,14 and both hypotonic and hypertonic aerosols.15
Significance of Airway Hyperresponsiveness Airway hyperresponsiveness can be demonstrated in almost all patients with current symptomatic asthma.3 Using the method described by Cockcroft et al,3 asthmatic subjects generally have a provocative concentration of a substance (histamine or methacholine) causing a 20% fall in FEV1 (PC20) of ⬍ 8 mg/mL. Most non-asthmatic patients will have a PC20 of ⬎ 16 mg/mL. There is, however, some overlap, and defining an exact level of airway responsiveness, which would distinguish asthmatic subjects from nonasthmatic subjects, is not possible. This is because there appears to be a continuous distribution of nonspecific airway responsiveness in the general popula-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
tion, with asthmatic subjects in one tail of this distribution.16 In addition, even subjects with normal histamine or methacholine airway responsiveness can develop symptoms of asthma if exposed to specific stimuli to which they are sensitized, such as an inhaled allergen or toluene diisocyanate.17 The severity of airway hyperresponsiveness generally correlates with the severity of asthma. The degree of airway hyperresponsiveness correlates with other important variables in asthma, such as variations in peak expiratory flow rates18 and with the improvement in FEV1 after receiving an inhaled bronchodilator.18 Last, the degree of airway constriction caused by exercise19 or the hyperventilation of cold, dry air in asthmatic subjects is related to the level of airway hyperresponsiveness.14 Airway hyperresponsiveness to inhaled histamine or methacholine has not just been demonstrated in asthmatic patients but also in patients with airflow obstruction apparently due to COPD.20 The degree of airflow obstruction, as indicated by the reduction in FEV1 and FEV1/VC ratio, correlates with the increase in airway responsiveness.20 This suggests that, in patients with airflow obstruction, the airway hyperresponsiveness demonstrated is a result of reduced airway caliber. By contrast, many patients with airway hyperresponsiveness and asthma have normal airway caliber at the time the inhalation challenge is being performed. This can, however, pose a problem in interpreting the result of an inhalation challenge with a constrictor agonist in a patient with significant airflow obstruction at the time of the study. The likelihood of identifying the presence of airway hyperresponsiveness in patients who are suspected of having asthma, based on history and physical examination, and in whom airway caliber is normal is only slightly better than chance alone, even by physicians who are experienced in treating asthma.21 Therefore, objective measurements of airway responsiveness are particularly useful in such patients with normal airway caliber in whom a diagnosis of asthma is being considered. Another important application of measuring airway responsiveness is the diagnosis of occupational asthma.22 The measurement of airway responsiveness also may be useful in determining the optimal treatment requirements of asthmatic patients. In a study by Sont et al,23 data from measurements of methacholine airway responsiveness were provided, in a randomized fashion, to physicians so that they could make decisions about the amounts of inhaled corticosteroids used to treat asthmatic patients. The doses of inhaled steroids in one group of patients were altered to attempt to normalize airway hyperresponsiveness, while in the other group standard clinical criteria were used. The study demonstrated that patients in whom efforts were made to optimize airway hyperresponsiveness required approximately twice the dose of inhaled corticosteroids, and this was associated with a significant reduction in the number of asthma exacerbations and a significant improvement in FEV1. Interestingly, the higher dose of inhaled steroids also caused a significant reduction in the layer of extracellular matrix proteins below the basement membrane. www.chestjournal.org
Genetics of Airway Hyperresponsiveness It has been recognized for many years that familial clustering exists for asthma, and more recently for airway hyperresponsiveness.24,25 This could reflect a genetic predisposition for the development of asthma, a shared environmental risk, or, most likely, a combination of both. Efforts also have been made to examine the genetic basis of airway hyperresponsiveness. Studies of monozygotic and dizygotic twins have suggested that there is a genetic basis for the development of airway hyperresponsiveness but that environmental factors are more important.26 Also, measurements of airway hyperresponsiveness in young infants (mean age, 4.5 weeks) have indicated that airway hyperresponsiveness can be present very early in life, and that a family history of asthma and parental smoking were risk factors for its development.27 More recently, reports of a genetic linkage of airway hyperresponsiveness have published. One study28 has identified genetic linkage between histamine airway hyperresponsiveness and several genetic markers on chromosome 5q, near a locus that regulates serum IgE levels. Another study has identified linkage between a highly polymorphic marker of the  subunit of the high-affinity IgE receptor on chromosome 11q and methacholine airway hyperresponsiveness, even in patients with nonatopic asthma.29 Thus, a genetic basis for airway hyperresponsiveness seems very likely. However, the genetic linkage studies need to be confirmed by other investigators in different patient populations. One specific gene polymorphism (Glu 27) of the nine identified of the 2-adrenoceptor also has been associated with increased methacholine airway hyperresponsiveness,30 while another polymorphism (Gly 16) has been associated with the presence of nocturnal asthma.31
Mechanisms of Airway Hyperresponsiveness Many different factors have been suggested to be involved in causing the airway hyperresponsiveness seen in asthma patients (Fig 2). Fundamentally, different inflammatory processes are thought to be important. It is believed that the increased number of eosinophils in asthmatic airways produce many of the tissue changes seen in the disease, including epithelial damage, thickening of the basement membrane, and the release of mediators with the capacity to cause bronchial smooth muscle contraction and exudation of plasma, resulting in thickening of the airway wall. Indeed, it is possible that a number of these different mechanisms interact to produce airway hyperresponsiveness, but it seems that different mechanisms are involved in causing different components of airway hyperresponsiveness. It is likely that one mechanism is responsible for the underlying airway hyperresponsiveness in asthmatic patients, differentiating them from healthy individuals, while another mechanism is important for the changes in airway hyperresponsiveness seen in asthmatic subjects during the course of the disease.
Persistent Airway Hyperresponsiveness It is likely that airway wall thickening, which has been described in patients with varying degrees of asthma CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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Figure 2. The hypothesis for the interaction of susceptibility genes and the environment in causing airway inflammation and airway hyperresponsiveness in asthma patients is shown.
severity, could explain some of the differences in airway hyperresponsiveness between healthy individuals and asthmatic patients. The thickness of the airway wall seen in autopsy specimens is greater in patients with fatal cases of asthma than in patients with milder disease and in nonasthmatic patients.32 It is not exactly clear which tissue contributes the most to airway wall thickening in asthma patients. One factor that may be involved is the subepithelial thickening seen in bronchial biopsy specimens from most asthmatic patients. Furthermore, bronchial smooth muscle may have a larger volume in asthmatic patients.33 Last, the exudation of plasma can cause edema and, thus, thickening of the airway wall. Together, these factors may, by geometric mechanisms, enhance the airway luminal resistance induced by a certain degree of airway smooth muscle shortening. Another feature of the asthmatic airway that correlates with the degree of airway hyperresponsiveness is loss of epithelial structure.34 Possibly, the partial loss of the epithelial barrier allows greater amounts of bronchoconstrictor mediators to reach the smooth muscle or other cells that amplify the bronchoconstricting effect of the inhaled mediators. Alternatively, the release of bronchodilating substances from the epithelium could be reduced by epithelial damage, which could enhance bronchial smooth muscle contraction.
Variable Airway Hyperresponsiveness Bronchial wall eosinophilic inflammation is a prominent feature of asthma. However, it is unlikely that ongoing eosinophilic inflammation by itself is the sole cause of 414S
airway hyperresponsiveness, because eliminating eosinophilic inflammation with inhaled corticosteroids improves, but does not eliminate, airway hyperresponsiveness. However, fluctuations in the extent of eosinophilic inflammation may underlie the changes in airway hyperresponsiveness that are seen during the course of the disease. This has been studied to a greater degree in clinical models of asthma, particularly allergen-induced asthma.35 Different forms of allergen exposure, such as challenge with a single dose of allergen,35,36 exposure to repeated low doses of allergen,37 or seasonal exposure to a pollen allergen,38 all increase eosinophilic airway inflammation, as judged by biopsy specimen, lavage sample, or induced sputum sample, as well as enhance the airway hyperresponsiveness already present in these asthmatic individuals. Furthermore, eliminating or decreasing the allergen load, by measures of allergen-avoidance, improves, but does not eliminate, airway hyperresponsiveness.39 Single high-dose allergen exposure, repeated low-dose allergen exposure, natural allergen exposure, and spontaneously occurring exacerbations of asthma all increase methacholine or histamine airway hyperresponsiveness by, on average, 1 to 2 doubling doses from a stable baseline. These changes in airway hyperresponsiveness are likely to be clinically significant, since they occur on top of the persisting airway hyperresponsiveness that is present in all asthmatic patients and that is associated with increases in the variability of lung function and in symptoms of asthma. While we have proposed that there may be separate mechanisms responsible for the underlying airway hyper-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
responsiveness of asthma and for the variability seen throughout the course of the diseases, it is quite likely that this distinction is not complete. It is likely that the underlying mechanisms responsible for inflammatory cell recruitment and mediator release may, in the short term, be responsible for variability in airway hyperresponsiveness, as well as, in the longer term, for the underlying structural changes that are responsible for persistent airway hyperresponsiveness.
Conclusions Measurements of airway responsiveness to inhaled bronchoconstrictor mediators (most often methacholine) can be useful in making a diagnosis of asthma, particularly in patients with symptoms that are consistent with asthma but who have no evidence of airflow obstruction. Methacholine inhalation tests can be performed quickly, safely, and reproducibly by experienced technicians, once the factors known to influence the tests are appropriately controlled for. Inhaled allergens initiate processes that increases airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (in the range of 1 to 2 doubling doses) are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects, in whom the differences are in the range of 4 to 8 doubling doses. These allergeninduced changes are, however, important, as they are similar to the changes occurring in asthmatic patients who already have airway hyperresponsiveness, which is associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatic patients. Nevertheless, the mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to explain the underlying mechanisms of persistent airway hyperresponsiveness in asthmatic patients.
References 1 Woolcock AJ, Salome CM, Yan K. The shape of the doseresponse curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 1984; 130:71–75 2 National Heart, Lung, and Blood Institute/National Institutes of Health. Global initiative for asthma. Bethesda, MD: National Heart, Lung, and Blood Institute/National Institutes of Health; 2002 NIH Publication No. 02–3659 3 Cockcroft DW, Killian DN, Mellon JJ, et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235–243 4 Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax 1981; 36:575–579 5 Alexander HL, Paddock R. Bronchial asthma: response to pilocarpine and epinephrine. Arch Intern Med 1921; 27:184– 191 www.chestjournal.org
6 Weiss S, Robb GP, Ellis LB. The systematic effects of histamine in man. Arch Intern Med 1932; 49:360 –396 7 Tiffeneau R, Beauvallet R. Epreuve de bronchoconstriction et de broncholilation par aerosols. Bull Acad Med 1945; 129:165–168 8 Curry JJ. The action of histamine on the respiratory tract of normal and asthmatic subjects. J Clin Invest 1946; 25:785–791 9 Adelroth E, Morris MM, Hargreave FE, et al. Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med 1986; 315:480 – 484 10 Hardy CC, Robinson C, Tattersfield AE, et al. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med 1984; 311:209 –213 11 Thomson NC, Roberts R, Bandouvakis J, et al. Comparison of bronchial responses to prostaglandin F2 alpha and methacholine. J Allergy Clin Immunol 1981; 68:392–398 12 Holgate ST, Mann JS, Cushley MJ. Adenosine as a bronchoconstrictor mediator in asthma and its antagonism by methylxanthines. J Allergy Clin Immunol 1984; 74:302–306 13 McFadden ER Jr, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994; 330:1362–1367 14 O’Byrne PM, Ryan G, Morris M, et al. Asthma induced by cold air and its relation to nonspecific bronchial responsiveness to methacholine. Am Rev Respir Dis 1982; 125:281–285 15 Anderson SD, Brannan J, Spring J, et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997; 156:758 –765 16 Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population. Chest 1983; 83:751–754 17 Hargreave FE, Ramsdale EH, Pugsley SO. Occupational asthma without bronchial hyperresponsiveness. Am Rev Respir Dis 1984; 130:513–515 18 Ryan G, Latimer KM, Dolovich J, et al. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway caliber. Thorax 1982; 37:423– 429 19 Anderton RC, Cuff MT, Frith PA, et al. Bronchial responsiveness to inhaled histamine and exercise. J Allergy Clin Immunol 1979; 63:315–320 20 Ramsdale EH, Morris MM, Roberts RS, et al. Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 1984; 39:912–918 21 Adelroth E, Hargreave FE, Ramsdale EH. Do physicians need objective measurements to diagnose asthma? Am Rev Respir Dis 1986; 134:704 –707 22 Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med 1995; 333:107–112 23 Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999; 159:1043–1051 24 Longo G, Strinati R, Poli F, et al. Genetic factors in nonspecific bronchial hyperreactivity. Am J Dis Child 1987; 141: 331–334 25 Hopp RJ, Bewtra A, Biven R, et al. Bronchial reactivity pattern in nonasthmatic parents of asthmatics. Ann Allergy 1988; 61:184 –186 26 Nieminen MM, Kaprio J, Koskenvuo M. A population based study of bronchial asthma in adult twin pairs. Chest 1991; 100:70 –75 CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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27 Young S, Le Souef PN, Geelhoed GC, et al. The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N Engl J Med 1991; 324: 1168 –1173 28 Postma DS, Bleeker ER, Amelung PJ, et al. Genetic susceptibility to asthma-bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333:894 –900 29 van Herwerden L, Harrap SB, Wong ZY, et al. Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in the absence of atopy. Lancet 1995; 346:1262–1265 30 Hall IP, Wheatley A, Wilding P, et al. Association of Glu 27 Beta 2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345:1213–1214 31 Turki J, Pak J, Green SA, et al. Genetic polymorphism of the beta-2 adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that Gly 16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:1635–1641 32 Pryor WA, Wu M. Ozonation of methyl oleate in hexane, in a thin film, in sds micelles, and in distearoylphosphatidylcholine liposomes: yields and properties of the criegee ozonide. Chem Res Toxicol 1992; 5:505–511 33 Dunnill MS, Massarell GR, Anderson JA. A comparison of the quantitive anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969; 24:176 –179 34 Jeffery PK, Wardlaw AJ, Nelson FC, et al. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140:1745–1753 35 Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999; 160:640 – 647 36 de Monchy JG, Kauffman HF, Venge P, et al. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 1985; 131:373–376 37 Sulakvelidze I, Inman MD, Rerecich TJ, et al. Increases in airway eosinophils and interleukin-5 with minimal bronchoconstriction during repeated low dose allergen challenge in atopic asthmatics. Eur Respir J 1998; 11:821– 827 38 Djukanovic R, Feather I, Gratziou C, et al. Effect of natural allergen exposure during the grass pollen season on airways inflammatory cells and asthma symptoms. Thorax 1996; 51: 575–581 39 Platts-Mills TA, Tovey ER, Mitchell EB, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982; 2:675– 678
inflammation and airway hyperresponsiveness A irway (AHR) are fundamental features of asthma. Migration
Intercellular Adhesion Molecule-1 Plays a Pivotal Role in Endotoxin-Induced Airway Disease*
Reference
David M. Brass, PhD; Jordan D. Savov, MD, PhD; and David A. Schwartz, MD, MPH, FCCP
(CHEST 2003; 123:416S) Abbreviations: AHR ⫽ airway hyperresponsiveness; ICAM ⫽ intercellular adhesion molecule 416S
of inflammatory cells from the circulation into the airways is mediated in part by adhesion molecules such as intercellular adhesion molecule (ICAM)-1, which are expressed on vascular endothelial cells, and the 2 integrin CD11b/CD18, which is expressed on neutrophils. Increasing evidence suggests that ICAM-1 and CD11b/CD18 also have signaling capabilities, suggesting that they might modulate airway reactivity independently of their adhesion properties. In previous studies from this laboratory1 we have demonstrated that antibodies to ICAM-1 and CD11b significantly reduced endotoxin-induced airway inflammation but did not affect AHR. To further define the separate contributions of ICAM-1 and CD11b/CD18 to endotoxin-induced inflammation and AHR, we exposed ICAM-1-deficient mice, CD18-deficient mice, and background strain control (ie, wild-type) mice to an aerosol of endotoxin for 4 h. Endotoxin-exposed, CD18-deficient mice showed no changes in AHR or neutrophilic inflammation in the lung compared to endotoxin-exposed, wildtype mice. However, while endotoxin-exposed ICAM-1deficient mice did not develop airway hyperreactivity, they mounted a normal inflammatory response to this toxin. The phenotypic differences that we observed in the ICAM-1-deficient mice and in the mice previously treated with ICAM-1 antibodies suggest that the IV administered ICAM-1 antibodies specifically prevent neutrophils from infiltrating the lung after endotoxin exposure but that reduced neutrophilic inflammation by itself has no effect on lipopolysaccharide endotoxin-induced AHR. Moreover, it appears that ICAM-1 is not required to facilitate the movement of neutrophils or polymorphonuclear leukocytes from the vascular space to the airspace, however, disruption of ICAM-1 prevents that development of lipopolysaccharide-induced AHR. In aggregate, our results suggest that ICAM-1 plays a pivotal role in the development of AHR and airway inflammation that are induced by endotoxin. Additionally, our results indicate that distinct mechanisms are responsible for the development of endotoxin-induced AHR and endotoxin-induced airway inflammation.
1 Moreland JG, Fuhrman RM, Pruessner JA, et al. CD11b and intercellular adhesion molecule-1 are involved in pulmonary neutrophil recruitment in lipopolysaccharide-induced airway disease. Am J Respir Cell Mol Biol 2002; 27:474 – 480 *From the Department of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC. This research was supported by National Institutes of Health grants ES11375, ES07498, and ES09607. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: David A. Schwartz, MD, MPH, FCCP, DUMC 2629, Room 275 MSRB, Research Drive, Durham, NC 27710; e-mail: [email protected]
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
Total Cell Count, Macrophages, Neutrophils, ⫻ 103 cells ⫻ 103 cells ⫻ 103 cells 43
27
16
167*
12
155*
41
28
14
38
25
12
131*
31
101*
41
26
16
*p ⬍ 0.05 compared to not sensitized/OVA challenged, OVA sensitized/RW challenged, not sensitized/RW challenged, and RW sensitized/OVA challenged.
Taken together, these results demonstrate that neutrophil influx after allergen challenge requires prior sensitization and is allergen-specific. Furthermore, we demonstrated that this transient neutrophil inflammation is mediated through the Fc␥ receptor (but not the Fc⑀RI) and is dependent on the presence of the antibody. The contribution of this early and transient neutrophil phase to the development of subsequent eosinophil and lymphocyte accumulation and to altered airway function events remains to be determined.
References 1 Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001; 344:350 –362 2 Wenzel SE, Szefler SJ, Leung DY, et al. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997; 156:737–743 3 Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991; 143:351–357 4 Tanizaki Y, Kitani H, Okazaki M, et al. Effects of long-term glucocorticoid therapy on bronchoalveolar cells in adult patients with bronchial asthma. J Asthma 1993; 30:309 –318 5 Fahy JV, Kim KW, Liu J, et al. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95:843– 852 6 Koh YY, Dupuid R, Pollice M, et al. Neutrophils recruited to the lungs of humans by segmental allergen challenge display a reduced chemotactic response to leukotriene B4. Am J Respir Cell Mol Biol 1993; 8:493– 499 7 Kelly EA, Busse WW, Jarjour NN. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med 2000; 162:1157–1161 8 Nocker RE, Out TA, Weller FR, et al. Influx of neutrophils into the airway lumen at 4 h after segmental allergen challenge in asthma. Int Arch Allergy Immunol 1999; 119: 45–53 9 Tomkinson A, Cieslewicz G, Duez C, et al. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. Am J Respir Crit Care Med 2001; 163:721–730 www.chestjournal.org
Airway Hyperresponsiveness* Paul M. O’Byrne, MB, FCCP; and Mark D. Inman, MD
Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Measurements of airway responsiveness are useful in making a diagnosis of asthma, particularly in patients who have symptoms that are consistent with asthma and who have no evidence of airflow obstruction. These tests can be performed quickly, safely, and reproducibly. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness. These changes in airway hyperresponsiveness are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects. They are, however, similar to changes occurring in asthmatic patients that are associated with worsening asthma control. The mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to fully explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients. (CHEST 2003; 123:411S– 416S) Abbreviation: PC20 ⫽ provocative concentration of a substance causing a 20% fall in FEV1
responsiveness is a term that describes the A irway ability of the airways to narrow after exposure to
constrictor agonists. Thus, airway hyperresponsiveness is an increased ability to develop this response. Airway hyperresponsiveness consists of an increased sensitivity of the airways to constrictor agonists, as indicated by a smaller concentration of a constrictor agonist needed to initiate the bronchoconstrictor response, a steeper slope of the dose-response, and a greater maximal response to the agonist (Fig 1).1 Airway responsiveness is measured using inhalation challenges with airway constrictor agonists, such as histamine or methacholine, in both clinical and research laboratories. This is because airway hyperresponsiveness has been identified as an important feature in patients with current, symptomatic asthma and, indeed, has been included in the defining characteristics of asthma.2 In addition, the severity of airway hyperresponsiveness cor-
*From the Firestone Institute for Respiratory Health, St. Joseph’s Hospital, Hamilton, ON, Canada. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Paul M. O’Byrne, MB, FCCP, Firestone Institute for Respiratory Health, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON, L8N 4A6 Canada; e-mail: obyrnep@ mcmaster.ca CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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Figure 1. The change in FEV1 vs baseline, induced by increasing doses of a bronchoconstrictor stimulus (methacholine) in patients with mild, moderate and severe asthma vs healthy individuals. The PC20 value is calculated by interpolating a 20% fall in FEV1 to the log-linear dose-response curve for each individual. Asthmatic subjects have a reduced threshold response (a), indicating increased sensitivity of the airways, an increased slope (b), indicating increased reactivity of the airways, and an increased maximal response (c).
relates with the severity of asthma3 and with the amount of treatment needed to control symptoms.4 The methods for measuring airway responsiveness have been standardized4 and are widely accepted.
Historical Perspective The initial observation that bronchoconstriction occurs more readily in asthmatic patients when compared to non-asthmatic patients after exposure to a constrictor agonist was made in 1921 by Alexander and Paddock,5 who demonstrated “asthmatic breathing” in asthmatic subjects, but not in healthy subjects, after subcutaneous administration of the cholinergic agonist pilocarpine. This observation was confirmed by Weiss et al6 in 1932, who reported that asthmatic subjects, but not healthy subjects, developed bronchoconstriction, as measured by changes in the vital capacity, after being given IV histamine. Tiffeneau and Beauvallet7 were the first to describe the use of acetylcholine inhalation tests to determine the degree of airway responsiveness in asthmatic patients, while Curry8 identified the fact that bronchoconstriction developed in asthmatic subjects after histamine was given intramuscularly, IV, or by nebulization.
Direct-Acting and Indirect-Acting Stimuli It is now known that airway hyperresponsiveness is present in asthmatic subjects to many chemical or physical stimuli other than inhaled histamine or the cholinergic 412S
agonists. These include chemical mediators such as cysteinyl leukotrienes C4 and D49 prostaglandin D210 and F2.11 All of these agonists cause bronchoconstriction by stimulating receptors that are present on airway smooth muscle. They are, therefore, considered to be directacting measures of airway responsiveness. An important distinction needs to be made between these methods of measuring airway responsiveness and indirect methods. Indirect-acting stimuli are those that cause bronchoconstriction in asthmatic patients by releasing constrictor mediators from cells in the airways. These stimuli include adenosine,12 exercise,13 hyperventilation of cold, dry air,14 and both hypotonic and hypertonic aerosols.15
Significance of Airway Hyperresponsiveness Airway hyperresponsiveness can be demonstrated in almost all patients with current symptomatic asthma.3 Using the method described by Cockcroft et al,3 asthmatic subjects generally have a provocative concentration of a substance (histamine or methacholine) causing a 20% fall in FEV1 (PC20) of ⬍ 8 mg/mL. Most non-asthmatic patients will have a PC20 of ⬎ 16 mg/mL. There is, however, some overlap, and defining an exact level of airway responsiveness, which would distinguish asthmatic subjects from nonasthmatic subjects, is not possible. This is because there appears to be a continuous distribution of nonspecific airway responsiveness in the general popula-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
tion, with asthmatic subjects in one tail of this distribution.16 In addition, even subjects with normal histamine or methacholine airway responsiveness can develop symptoms of asthma if exposed to specific stimuli to which they are sensitized, such as an inhaled allergen or toluene diisocyanate.17 The severity of airway hyperresponsiveness generally correlates with the severity of asthma. The degree of airway hyperresponsiveness correlates with other important variables in asthma, such as variations in peak expiratory flow rates18 and with the improvement in FEV1 after receiving an inhaled bronchodilator.18 Last, the degree of airway constriction caused by exercise19 or the hyperventilation of cold, dry air in asthmatic subjects is related to the level of airway hyperresponsiveness.14 Airway hyperresponsiveness to inhaled histamine or methacholine has not just been demonstrated in asthmatic patients but also in patients with airflow obstruction apparently due to COPD.20 The degree of airflow obstruction, as indicated by the reduction in FEV1 and FEV1/VC ratio, correlates with the increase in airway responsiveness.20 This suggests that, in patients with airflow obstruction, the airway hyperresponsiveness demonstrated is a result of reduced airway caliber. By contrast, many patients with airway hyperresponsiveness and asthma have normal airway caliber at the time the inhalation challenge is being performed. This can, however, pose a problem in interpreting the result of an inhalation challenge with a constrictor agonist in a patient with significant airflow obstruction at the time of the study. The likelihood of identifying the presence of airway hyperresponsiveness in patients who are suspected of having asthma, based on history and physical examination, and in whom airway caliber is normal is only slightly better than chance alone, even by physicians who are experienced in treating asthma.21 Therefore, objective measurements of airway responsiveness are particularly useful in such patients with normal airway caliber in whom a diagnosis of asthma is being considered. Another important application of measuring airway responsiveness is the diagnosis of occupational asthma.22 The measurement of airway responsiveness also may be useful in determining the optimal treatment requirements of asthmatic patients. In a study by Sont et al,23 data from measurements of methacholine airway responsiveness were provided, in a randomized fashion, to physicians so that they could make decisions about the amounts of inhaled corticosteroids used to treat asthmatic patients. The doses of inhaled steroids in one group of patients were altered to attempt to normalize airway hyperresponsiveness, while in the other group standard clinical criteria were used. The study demonstrated that patients in whom efforts were made to optimize airway hyperresponsiveness required approximately twice the dose of inhaled corticosteroids, and this was associated with a significant reduction in the number of asthma exacerbations and a significant improvement in FEV1. Interestingly, the higher dose of inhaled steroids also caused a significant reduction in the layer of extracellular matrix proteins below the basement membrane. www.chestjournal.org
Genetics of Airway Hyperresponsiveness It has been recognized for many years that familial clustering exists for asthma, and more recently for airway hyperresponsiveness.24,25 This could reflect a genetic predisposition for the development of asthma, a shared environmental risk, or, most likely, a combination of both. Efforts also have been made to examine the genetic basis of airway hyperresponsiveness. Studies of monozygotic and dizygotic twins have suggested that there is a genetic basis for the development of airway hyperresponsiveness but that environmental factors are more important.26 Also, measurements of airway hyperresponsiveness in young infants (mean age, 4.5 weeks) have indicated that airway hyperresponsiveness can be present very early in life, and that a family history of asthma and parental smoking were risk factors for its development.27 More recently, reports of a genetic linkage of airway hyperresponsiveness have published. One study28 has identified genetic linkage between histamine airway hyperresponsiveness and several genetic markers on chromosome 5q, near a locus that regulates serum IgE levels. Another study has identified linkage between a highly polymorphic marker of the  subunit of the high-affinity IgE receptor on chromosome 11q and methacholine airway hyperresponsiveness, even in patients with nonatopic asthma.29 Thus, a genetic basis for airway hyperresponsiveness seems very likely. However, the genetic linkage studies need to be confirmed by other investigators in different patient populations. One specific gene polymorphism (Glu 27) of the nine identified of the 2-adrenoceptor also has been associated with increased methacholine airway hyperresponsiveness,30 while another polymorphism (Gly 16) has been associated with the presence of nocturnal asthma.31
Mechanisms of Airway Hyperresponsiveness Many different factors have been suggested to be involved in causing the airway hyperresponsiveness seen in asthma patients (Fig 2). Fundamentally, different inflammatory processes are thought to be important. It is believed that the increased number of eosinophils in asthmatic airways produce many of the tissue changes seen in the disease, including epithelial damage, thickening of the basement membrane, and the release of mediators with the capacity to cause bronchial smooth muscle contraction and exudation of plasma, resulting in thickening of the airway wall. Indeed, it is possible that a number of these different mechanisms interact to produce airway hyperresponsiveness, but it seems that different mechanisms are involved in causing different components of airway hyperresponsiveness. It is likely that one mechanism is responsible for the underlying airway hyperresponsiveness in asthmatic patients, differentiating them from healthy individuals, while another mechanism is important for the changes in airway hyperresponsiveness seen in asthmatic subjects during the course of the disease.
Persistent Airway Hyperresponsiveness It is likely that airway wall thickening, which has been described in patients with varying degrees of asthma CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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Figure 2. The hypothesis for the interaction of susceptibility genes and the environment in causing airway inflammation and airway hyperresponsiveness in asthma patients is shown.
severity, could explain some of the differences in airway hyperresponsiveness between healthy individuals and asthmatic patients. The thickness of the airway wall seen in autopsy specimens is greater in patients with fatal cases of asthma than in patients with milder disease and in nonasthmatic patients.32 It is not exactly clear which tissue contributes the most to airway wall thickening in asthma patients. One factor that may be involved is the subepithelial thickening seen in bronchial biopsy specimens from most asthmatic patients. Furthermore, bronchial smooth muscle may have a larger volume in asthmatic patients.33 Last, the exudation of plasma can cause edema and, thus, thickening of the airway wall. Together, these factors may, by geometric mechanisms, enhance the airway luminal resistance induced by a certain degree of airway smooth muscle shortening. Another feature of the asthmatic airway that correlates with the degree of airway hyperresponsiveness is loss of epithelial structure.34 Possibly, the partial loss of the epithelial barrier allows greater amounts of bronchoconstrictor mediators to reach the smooth muscle or other cells that amplify the bronchoconstricting effect of the inhaled mediators. Alternatively, the release of bronchodilating substances from the epithelium could be reduced by epithelial damage, which could enhance bronchial smooth muscle contraction.
Variable Airway Hyperresponsiveness Bronchial wall eosinophilic inflammation is a prominent feature of asthma. However, it is unlikely that ongoing eosinophilic inflammation by itself is the sole cause of 414S
airway hyperresponsiveness, because eliminating eosinophilic inflammation with inhaled corticosteroids improves, but does not eliminate, airway hyperresponsiveness. However, fluctuations in the extent of eosinophilic inflammation may underlie the changes in airway hyperresponsiveness that are seen during the course of the disease. This has been studied to a greater degree in clinical models of asthma, particularly allergen-induced asthma.35 Different forms of allergen exposure, such as challenge with a single dose of allergen,35,36 exposure to repeated low doses of allergen,37 or seasonal exposure to a pollen allergen,38 all increase eosinophilic airway inflammation, as judged by biopsy specimen, lavage sample, or induced sputum sample, as well as enhance the airway hyperresponsiveness already present in these asthmatic individuals. Furthermore, eliminating or decreasing the allergen load, by measures of allergen-avoidance, improves, but does not eliminate, airway hyperresponsiveness.39 Single high-dose allergen exposure, repeated low-dose allergen exposure, natural allergen exposure, and spontaneously occurring exacerbations of asthma all increase methacholine or histamine airway hyperresponsiveness by, on average, 1 to 2 doubling doses from a stable baseline. These changes in airway hyperresponsiveness are likely to be clinically significant, since they occur on top of the persisting airway hyperresponsiveness that is present in all asthmatic patients and that is associated with increases in the variability of lung function and in symptoms of asthma. While we have proposed that there may be separate mechanisms responsible for the underlying airway hyper-
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium
responsiveness of asthma and for the variability seen throughout the course of the diseases, it is quite likely that this distinction is not complete. It is likely that the underlying mechanisms responsible for inflammatory cell recruitment and mediator release may, in the short term, be responsible for variability in airway hyperresponsiveness, as well as, in the longer term, for the underlying structural changes that are responsible for persistent airway hyperresponsiveness.
Conclusions Measurements of airway responsiveness to inhaled bronchoconstrictor mediators (most often methacholine) can be useful in making a diagnosis of asthma, particularly in patients with symptoms that are consistent with asthma but who have no evidence of airflow obstruction. Methacholine inhalation tests can be performed quickly, safely, and reproducibly by experienced technicians, once the factors known to influence the tests are appropriately controlled for. Inhaled allergens initiate processes that increases airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (in the range of 1 to 2 doubling doses) are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects, in whom the differences are in the range of 4 to 8 doubling doses. These allergeninduced changes are, however, important, as they are similar to the changes occurring in asthmatic patients who already have airway hyperresponsiveness, which is associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatic patients. Nevertheless, the mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to explain the underlying mechanisms of persistent airway hyperresponsiveness in asthmatic patients.
References 1 Woolcock AJ, Salome CM, Yan K. The shape of the doseresponse curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 1984; 130:71–75 2 National Heart, Lung, and Blood Institute/National Institutes of Health. Global initiative for asthma. Bethesda, MD: National Heart, Lung, and Blood Institute/National Institutes of Health; 2002 NIH Publication No. 02–3659 3 Cockcroft DW, Killian DN, Mellon JJ, et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235–243 4 Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax 1981; 36:575–579 5 Alexander HL, Paddock R. Bronchial asthma: response to pilocarpine and epinephrine. Arch Intern Med 1921; 27:184– 191 www.chestjournal.org
6 Weiss S, Robb GP, Ellis LB. The systematic effects of histamine in man. Arch Intern Med 1932; 49:360 –396 7 Tiffeneau R, Beauvallet R. Epreuve de bronchoconstriction et de broncholilation par aerosols. Bull Acad Med 1945; 129:165–168 8 Curry JJ. The action of histamine on the respiratory tract of normal and asthmatic subjects. J Clin Invest 1946; 25:785–791 9 Adelroth E, Morris MM, Hargreave FE, et al. Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med 1986; 315:480 – 484 10 Hardy CC, Robinson C, Tattersfield AE, et al. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med 1984; 311:209 –213 11 Thomson NC, Roberts R, Bandouvakis J, et al. Comparison of bronchial responses to prostaglandin F2 alpha and methacholine. J Allergy Clin Immunol 1981; 68:392–398 12 Holgate ST, Mann JS, Cushley MJ. Adenosine as a bronchoconstrictor mediator in asthma and its antagonism by methylxanthines. J Allergy Clin Immunol 1984; 74:302–306 13 McFadden ER Jr, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994; 330:1362–1367 14 O’Byrne PM, Ryan G, Morris M, et al. Asthma induced by cold air and its relation to nonspecific bronchial responsiveness to methacholine. Am Rev Respir Dis 1982; 125:281–285 15 Anderson SD, Brannan J, Spring J, et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997; 156:758 –765 16 Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population. Chest 1983; 83:751–754 17 Hargreave FE, Ramsdale EH, Pugsley SO. Occupational asthma without bronchial hyperresponsiveness. Am Rev Respir Dis 1984; 130:513–515 18 Ryan G, Latimer KM, Dolovich J, et al. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway caliber. Thorax 1982; 37:423– 429 19 Anderton RC, Cuff MT, Frith PA, et al. Bronchial responsiveness to inhaled histamine and exercise. J Allergy Clin Immunol 1979; 63:315–320 20 Ramsdale EH, Morris MM, Roberts RS, et al. Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 1984; 39:912–918 21 Adelroth E, Hargreave FE, Ramsdale EH. Do physicians need objective measurements to diagnose asthma? Am Rev Respir Dis 1986; 134:704 –707 22 Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med 1995; 333:107–112 23 Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999; 159:1043–1051 24 Longo G, Strinati R, Poli F, et al. Genetic factors in nonspecific bronchial hyperreactivity. Am J Dis Child 1987; 141: 331–334 25 Hopp RJ, Bewtra A, Biven R, et al. Bronchial reactivity pattern in nonasthmatic parents of asthmatics. Ann Allergy 1988; 61:184 –186 26 Nieminen MM, Kaprio J, Koskenvuo M. A population based study of bronchial asthma in adult twin pairs. Chest 1991; 100:70 –75 CHEST / 123 / 3 / MARCH, 2003 SUPPLEMENT
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27 Young S, Le Souef PN, Geelhoed GC, et al. The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N Engl J Med 1991; 324: 1168 –1173 28 Postma DS, Bleeker ER, Amelung PJ, et al. Genetic susceptibility to asthma-bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995; 333:894 –900 29 van Herwerden L, Harrap SB, Wong ZY, et al. Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in the absence of atopy. Lancet 1995; 346:1262–1265 30 Hall IP, Wheatley A, Wilding P, et al. Association of Glu 27 Beta 2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345:1213–1214 31 Turki J, Pak J, Green SA, et al. Genetic polymorphism of the beta-2 adrenergic receptor in nocturnal and nonnocturnal asthma: evidence that Gly 16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:1635–1641 32 Pryor WA, Wu M. Ozonation of methyl oleate in hexane, in a thin film, in sds micelles, and in distearoylphosphatidylcholine liposomes: yields and properties of the criegee ozonide. Chem Res Toxicol 1992; 5:505–511 33 Dunnill MS, Massarell GR, Anderson JA. A comparison of the quantitive anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969; 24:176 –179 34 Jeffery PK, Wardlaw AJ, Nelson FC, et al. Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989; 140:1745–1753 35 Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999; 160:640 – 647 36 de Monchy JG, Kauffman HF, Venge P, et al. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 1985; 131:373–376 37 Sulakvelidze I, Inman MD, Rerecich TJ, et al. Increases in airway eosinophils and interleukin-5 with minimal bronchoconstriction during repeated low dose allergen challenge in atopic asthmatics. Eur Respir J 1998; 11:821– 827 38 Djukanovic R, Feather I, Gratziou C, et al. Effect of natural allergen exposure during the grass pollen season on airways inflammatory cells and asthma symptoms. Thorax 1996; 51: 575–581 39 Platts-Mills TA, Tovey ER, Mitchell EB, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982; 2:675– 678
inflammation and airway hyperresponsiveness A irway (AHR) are fundamental features of asthma. Migration
Intercellular Adhesion Molecule-1 Plays a Pivotal Role in Endotoxin-Induced Airway Disease*
Reference
David M. Brass, PhD; Jordan D. Savov, MD, PhD; and David A. Schwartz, MD, MPH, FCCP
(CHEST 2003; 123:416S) Abbreviations: AHR ⫽ airway hyperresponsiveness; ICAM ⫽ intercellular adhesion molecule 416S
of inflammatory cells from the circulation into the airways is mediated in part by adhesion molecules such as intercellular adhesion molecule (ICAM)-1, which are expressed on vascular endothelial cells, and the 2 integrin CD11b/CD18, which is expressed on neutrophils. Increasing evidence suggests that ICAM-1 and CD11b/CD18 also have signaling capabilities, suggesting that they might modulate airway reactivity independently of their adhesion properties. In previous studies from this laboratory1 we have demonstrated that antibodies to ICAM-1 and CD11b significantly reduced endotoxin-induced airway inflammation but did not affect AHR. To further define the separate contributions of ICAM-1 and CD11b/CD18 to endotoxin-induced inflammation and AHR, we exposed ICAM-1-deficient mice, CD18-deficient mice, and background strain control (ie, wild-type) mice to an aerosol of endotoxin for 4 h. Endotoxin-exposed, CD18-deficient mice showed no changes in AHR or neutrophilic inflammation in the lung compared to endotoxin-exposed, wildtype mice. However, while endotoxin-exposed ICAM-1deficient mice did not develop airway hyperreactivity, they mounted a normal inflammatory response to this toxin. The phenotypic differences that we observed in the ICAM-1-deficient mice and in the mice previously treated with ICAM-1 antibodies suggest that the IV administered ICAM-1 antibodies specifically prevent neutrophils from infiltrating the lung after endotoxin exposure but that reduced neutrophilic inflammation by itself has no effect on lipopolysaccharide endotoxin-induced AHR. Moreover, it appears that ICAM-1 is not required to facilitate the movement of neutrophils or polymorphonuclear leukocytes from the vascular space to the airspace, however, disruption of ICAM-1 prevents that development of lipopolysaccharide-induced AHR. In aggregate, our results suggest that ICAM-1 plays a pivotal role in the development of AHR and airway inflammation that are induced by endotoxin. Additionally, our results indicate that distinct mechanisms are responsible for the development of endotoxin-induced AHR and endotoxin-induced airway inflammation.
1 Moreland JG, Fuhrman RM, Pruessner JA, et al. CD11b and intercellular adhesion molecule-1 are involved in pulmonary neutrophil recruitment in lipopolysaccharide-induced airway disease. Am J Respir Cell Mol Biol 2002; 27:474 – 480 *From the Department of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC. This research was supported by National Institutes of Health grants ES11375, ES07498, and ES09607. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: David A. Schwartz, MD, MPH, FCCP, DUMC 2629, Room 275 MSRB, Research Drive, Durham, NC 27710; e-mail: [email protected]
Thomas L. Petty 45th Annual Aspen Lung Conference: Asthma in the New Millennium