Professional Documents
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Asthma
One Hundred Years of Treatment and Onward
Eric K. Chu and Jeffrey M. Drazen
Pulmonary Division, Department of Medicine, Brigham and Womens Hospital; and Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
There have been four types of drug treatment of asthma that have been used over the past 100 years. Belladonna alkaloids, derived from the thorn-apple plant were used in 1905, and chemically synthesized entities in this class are still in use today. Western medicine began to use adrenergic stimulants approximately 100 years ago, but they were likely used in Asian medicine long before that. Systemic treatment with corticosteroids was introduced into the treatment of asthma in the mid-20th century; inhaled corticosteroids have been in use for over 35 years. The last 40 years have also seen the development of the first targeted asthma treatments: cromones, antileukotrienes, and anti-IgE. As we learn more of the biology of asthma, we anticipate that more effective targeted asthma treatments will be developed. Keywords: adrenergic; anticholinergic; asthma; corticosteroid
This article examines the evolution of the treatment of asthma by environmental manipulation and drug treatments over the past 100 years. Because we want to identify the most commonly used general practices until the late 20th century, we take most of our guidance from generally accepted textbooks of medicine. We also have tried to identify the key contributions that led to the evolution of asthma treatment.
Although asthma has been described as a medical entity since the time of Aretaeus, the Cappadocian, in approximately 100 a.d. (see review by Marketos and Ballas [1]), the constellation of physical ndings and signs that we currently recognize as asthma dates from the work of John Floyer (2) in 1698. Floyer dened asthma as laborious respiration with lifting of the shoulders and wheezing. He understood that asthma was intermittent and episodic and that the treatment of asthma needs to consist of rescue and controller therapy, termed by him as treatment both in t and out of it. By 1900, it was well established that certain forms of asthma could be brought on by exposure to environmental allergens. In Stedmans Twentieth Century Practice, published in 1896, Sir Thomas Granger Stewart and George Alexander Gibson (3) wrote about asthma:
The treatment of asthma involves the treatment of the patient during ts and between the ts. The general indications are: 1. To allay the spasm during the paroxysm; 2. To nd out and remove the exciting cause . . . 3. To treat complications and sequelae and to improve the general health.
Thus, more than 100 years ago, the general approach to asthma treatment was then as it is now: acute rescue treatment, controller treatment, and prevention of long-term complications.
(Received in original form February 16, 2005; accepted in final form March 16, 2005) Correspondence and requests for reprints should be addressed to Jeffrey M. Drazen, M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115. E-mail: jdrazen@nejm.org
Am J Respir Crit Care Med Vol 171. pp 12021208, 2005 Originally Published in Press as DOI: 10.1164/rccm.200502-257OE on March 18, 2005 Internet address: www.atsjournals.org
ASTHMA PHARMACOTHERAPY
There are four general types of pharmacologic treatment that have been used for asthma over the past 100 years. Interestingly,
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most of the treatments, once introduced, have remained in the pharmacopeia, although the specic entities and methods of delivery have changed. These four overlapping epochs of the pharmacologic treatment of asthma are as follows: (1) the use of anticholinergic belladonna-related alkaloids; (2) the use of nonanti-cholinergic bronchodilator stimulation; (3) the use of corticosteroids; and (4) the use of specically targeted asthma treatmentsnamely, cromones, antileukotrienes, and anti-IgE. Each of these will be considered separately.
These data show that the use of belladonna alkaloids has been advocated in the treatment of asthma for more than 100 years. The mechanism of effect is not known with precision but is likely the inhibition of reex bronchoconstriction mediated via cholinergic pathways.
NONANTI-CHOLINERGIC BRONCHODILATORS
Methyl Xanthines
Stramonium is the dried leaf and the owering or fruiting tops of the plant, Datura stramonium. This is also referred to as the thorn-apple plant. The active ingredients in this were alkaloids of belladonna, which we now know had the effect of inhibiting cholinergic neurotransmission and thereby reex bronchoconstriction. In 1914, in the eighth edition of the Principles and Practice of Medicine, Osler (8) points out that hypodermic injections of pilocarpine can be effective in the treatment of asthma. He also claims that the sedative antispasmodics, such as belladonna, may be given in solution or used in the form of cigarettes. Nearly all the popular remedies either in this form or in pastilles contain some plant of the order Solanaceae . . . . Excellent cigarettes are now manufactured and asthmatics try various sorts since one form benets one patient, another form another patient. Thus, in 1914, anticholinergics by injection or inhalation were considered as rst-line asthma therapies. Osler also made the important observation of the intraindividual differences in the response to asthma treatment. We now appreciate that these differences may reect genetic variations in the mechanisms leading to the asthmatic response among subjects. In the 1927 edition of Cecils A Text-book of Medicine, Francis Rackemann (9) again suggests the use of the smoke of stramonium leaves, atropine, and belladonna. In the seventh edition of Cecils A Textbook of Medicine, published in 1947, Rackemann (10) still suggests the use of asthma powders or asthma cigarettes with the active ingredient consisting of belladonnatype alkaloids. However, by 1975, when the 14th edition of the textbook was published, belladonna alkaloids were not considered a signicant enough part of asthma treatment to be included by J.B.L. Howell (11). The treatment of asthma with ipratropium bromide, a stable atropine-like compound, was introduced in the 1980s (12). Although its use in asthma rescue treatment has not been approved by the U.S. Food and Drug Administration, it was used successfully in a recent study sponsored by the National Institutes of Health Asthma Clinical Research Network (13), as an asthma rescue therapy in patients with mild intermittent asthma. This was necessary because the study identied a subset of patients with asthma who had adverse responses to adrenergic bronchodilators, and it was therefore necessary to manage these patients with a nonadrenergic bronchodilator, such as ipratropium bromide.
Bronchodilators other than belladonna alkaloids were not mentioned in Stedmans 1896 textbook or in Oslers 1914 edition of the Principles and Practice of Medicine; although in that latter work, coffee is recommended as a treatment for asthma. There is no mention by Rackemann of the use of theophylline, or related compounds, in the fourth edition (published in 1937) of Cecils Textbook of Medicine (14), but in the fth edition (1940), this treatment is mentioned (15): Aminophylline in doses of 0.25 Gm. dissolved in 10 cc. of water is often very effective when injected intravenously. From that time forward into the present, methyl xanthines have been used, most often in the form of theophylline or the water-soluble, related compound aminophylline, for the treatment of asthma. Although the mechanism of action of these agents is not established with certainty, they are bronchodilators by virtue of their ability to inhibit phosphodiesterase and thus to inhibit the breakdown of cyclic AMP. However, they have many other potential mechanisms of action in asthma, and a full review of their use in asthma is beyond the scope of this article; readers are referred to authoritative reviews by others (16). Theophylline continues to be an inexpensive and effective asthma treatment. However, it has a low ratio of therapeutic benet to potentially toxic side effects. Dosing needs to be carefully monitored to be sure that a given patient is receiving the benets of treatment without its side effects. To complicate matters, theophylline metabolism varies substantially both among individuals and in a given subject. Even when an effective dose is established, it is important to continue to monitor plasma drug levels. Given these difculties, many consider that theophylline is not a rst-line asthma therapy.
Direct Adrenergic Bronchodilators
Direct adrenergic bronchodilators were introduced in Western medicine for the treatment of asthmatic attacks in the early 1900s. In an article in the Lancet in 1910, Melland (17) described dramatic responses to adrenaline injection in three patients with asthma who were unresponsive to usual asthma treatment. In 1926, Thomas (18) described the use of ephedrine in asthma, but it is highly likely that this treatment had already been used in China for centuries. When the seventh edition of Cecils Textbook of Medicine was published, Rackemann (9) wrote,
The treatment of an attack is usually simple. Adrenalin chloride injected subcutaneously can control almost any attack from a time varying from minutes to hours. The dose of 0.25 c.c. of a 1:1000 solution often works as well as 1.0 c.c. The dose can be repeated at half-hour intervals if necessary.
In the 1947 edition, Rackemann (10) amended this statement to suggest that epinephrine could be given by inhalation of a 1:100 solution to relieve asthmatic bronchoconstriction (Figure 2). By the mid-1950s, metered-dose inhalers had been devised for the delivery of epinephrine and isoproterenol, the latter being a relatively specic -adrenergic agonist. These inhalers were widely used for asthma treatment; they are still in use today, even though there are bronchodilators available with fewer side effects.
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Figure 1. Asthma cigarettes were used to deliver alkaloids with bronchodilator properties. They were sold commercially for asthma treatment until just before the middle of the 20th century. (Courtesy of Mark Saunders and his Inhalatorium, www.inhalatorium.com.)
However, there were signicant adverse effects associated with this treatment. There was an epidemic of asthma deaths that occurred in Britain during the mid-20th century. Analysis of epidemiologic data suggested that this epidemic was associated with the widespread use of isoproterenol fortea highstrength isoproterenol solution packaged in the metered-dose inhaler (19, 20). The epidemic abated when the high potency inhaler was withdrawn from the market and a physician education campaign to be sure that patients with asthma were adequately treated was launched. Because the actions were taken together, it is impossible to know with condence which was responsible for the improved outcomes.
In the 1960s and 1970s, relatively specic 2-adrenergic agonists were developed for use by inhalation (21). Albuterol (known outside the United States as salbutamol), metaproterenol, isoetherine, terbutaline, and others were introduced into the marketplace. These agents had rapid onset of action, produced bronchodilation lasting 4 to 6 hours, and became the bronchodilator of choice. Since the mid-1980s, bronchoconstriction that could be relieved by the inhalation of a specic 2 agonist was commonly included as a diagnostic criterion of asthma. Rossing and others (22) showed that inhalation of selective 2 agonists was equally, if not more, effective than injection of subcutaneous epinephrine for the relief of the airway obstruction associated with acute asthma attacks. Eventually this led to the widespread
Figure 2. The use of inhaled adrenaline to treat asthma began in the first third of the 20th century and continues to this day. The images show an early nebulizer marketed for the treatment of asthma. (Courtesy of Mark Saunders and his Inhalatorium, www.inhalatorium.com.)
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use of inhaled selective 2 bronchodilators as the primary treatment of acute asthmatic airway obstruction. The adrenergic bronchodilator armamentarium has advanced with the development of selective 2 agonists that were engineered to provide a long duration of bronchodilator activity. Long-acting bronchodilators, such as fenoterol, formoterol, and salmeterol, were introduced into the marketplace worldwide for use in the control of asthma symptoms (23). These agents are effective bronchodilators, but a number of studies have shown that they should not be used as the sole agents for the treatment of asthma, but rather should be used in a coordinated program of asthma medications, which includes agents such as inhaled corticosteroids or leukotriene antagonists (24, 25). In the past 4 years, there have been data available to suggest that a proportion of patients who regularly use selective 2-adrenergic agonists, such as albuterol, may develop residual bronchoconstriction many hours after the acute bronchodilator effect of the medication has worn off. Findings from retrospective analyses (26, 27) and a double-blind, randomized, placebocontrolled, genotype-stratied crossover trial indicate that patients possessing the Arg-Arg genotype, at position 16 of the 2-adrenergic receptor, are at risk for developing this residual bronchoconstriction (13). Not only is this manifested by lower ow rates but patients with this genotype had increased asthma symptoms and increased asthma medication use during the period of regular treatment with albuterol, compared with placebo in patients harboring the Arg-Arg genotype as well as compared with patients with the GLY-GLY genotype at position 16 of the 2-adrenergic receptor. Although these data need to be replicated in a larger trial powered on asthma exacerbations, it makes sense to consider alternative asthma action plans for patients who appear to develop adverse effects when treated with 2adrenergic agonists on a regular basis.
CORTICOSTEROIDS
Corticosteroids were not generally available for medicinal use until the late 1940s. In the early 1950s, anecdotal case reports showed that treatment with adrenal corticotropic hormone or corticosteroids resulted in an improvement in asthma. For example, McCombs (28) described ve cases of asthma refractory to treatment with standard therapy that had a signicant response to systemic treatment with corticosteroids or adrenal corticotropic hormone (Figure 3). He wrote, There is no doubt that in the ve cases herein reported corticotropin and cortisone brought about changes that could not have been produced so regularly by any other known method of treatment. By the 1970s, systemic corticosteroids had been accepted as the standard therapy to both treat and prevent asthma exacerbations. For
patients with severe asthma, either the use of daily or everyother-day oral corticosteroids was considered state-of-the-art therapy. The major issues were how to treat asthma in patients with disease of moderate severity without encumbering the severe side effects associated with daily corticosteroid therapy. The solution to this problem came in the form of inhaled corticosteroids. Brown and colleagues (29) reported that patients who were dependent on oral corticosteroids could be switched to inhaled corticosteroids (Figure 4). Later, a large trial organized by the British Thoracic Society showed that steroid-naive patients with moderate to severe asthma could be controlled with this treatment (30). Although these studies were widely conrmed (31, 32), physicians and patients were slow to adopt their use, perhaps because their effects on the airways were delayed compared with those achieved with bronchodilators. However, over time, it became clear that they were effective asthma treatments and safe relative to the use of systemic corticosteroids. The study that had the biggest impact on the use of inhaled corticosteroids was that of Haahtela and coworkers (33). In this trial, patients with newly diagnosed asthma were randomly assigned to receive inhaled corticosteroids or an inhaled 2 agonist as their primary asthma treatment for 2 years. Over the period of the trial, there was less bronchial responsiveness among the patients treated with inhaled corticosteroids than there was among the patients treated with terbutaline. In a follow-up study, patients who had been assigned to terbutaline were assigned to corticosteroids and experienced a smaller degree of improvement than those who had started on corticosteroids, suggesting that treatment early on was more effective than treatment later into the course of asthma (34). However, this study was not designed to directly test the critical question: Would the regular use of inhaled corticosteroids modify the long-term effects of asthma? There have been two large long-term studies that have been designed to do so. In the Childhood Asthma Management Program (CAMP) study, children, aged 7 to 12 years at onset, were assigned to treatment with inhaled corticosteroids, nedocromil, or placebo on a daily basis (35). There were no differences over the 5 years of study with respect to the rate of loss of lung function between the groups, whereas there were differences, in favor of inhaled budesonide, in the time to rst asthma exacerbation. These data indicated that corticosteroids were effective at preventing asthma paroxysms but did not modify the underlying loss of lung function associated with chronic asthma. In a double-blind, randomized, placebo-controlled trial, adults and children with newly diagnosed asthma were assigned to treatment with inhaled budesonide or placebo (36). As in the CAMP trial, there were fewer
Figure 3. A pictorial description of Case 3 as reported by McCombs (28). The height of the smooth curved line denotes asthma severity, whereas the height of the bars denotes the number of milligrams of cortisone or units of adrenal corticotropic hormone (ACTH) used in treatment. Redrawn and reprinted by permission from Reference 28.
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Figure 4. Case example of the effectiveness of inhaled corticosteroids from the original report of Brown and coworkers (Reprinted by permission from Reference 29). The case legend from Brown and coworkers reads as follows: Man aged 45. Late onset asthma-allergens unknown. A good example of the usefulness of aerosol therapy until airways cleared by high-dosage corticosteroids. Disodium cromoglycate (DSCG) had been used for a year but was no longer effective. High level [of function] maintained to date on aerosol alone. The aerosol actually caused bronchospasm when first introduced.
asthma exacerbations in the group assigned to budesonide. There was an overall 0.88% improvement, in lung function expressed as a percentage of predicted value, over time in favor of budesonide, but the effects were not consistent over age groups, raising questions as to the robustness of the ndings. Inhaled corticosteroids have side effects. When used on a regular basis for long periods of time, there are documented adverse effects, such as loss of stature (35, 36), decreased bone mineralization, glaucoma, and cataracts (3739). Inhaled corticosteroids have been recommended and used in the treatment of asthma for just over 30 years; they are very effective as asthmacontroller therapies, but there are no convincing data that they are disease-modifying treatments.
cromoglycate, which was eventually marketed as an antiasthmatic drug. Both it and another drug in the same family, nedocromil sodium, are available as asthma treatments (40, 41) but are used most frequently in children. Although these agents were discovered by searching for drugs with antiasthmatic effects, and in that sense are targeted treatments, their exact mechanism of antiallergic action is not known with certainty. In contrast, antileukotriene and anti-IgE treatments for asthma were developed to target specic known pathobiologies of asthma. The antileukotrienes were developed to block the potent biological bronchoconstrictor, previously known as slow-reacting substance of anaphylaxis, or SRS-A, and now appreciated to be a mixture of the acidic lipids, leukotrienes, C4, D4, and E4 (42). The role of these substances in asthma seemed reasonable because they are released by mast cells during anaphylactic reactions and because of their potent bronchoconstrictor properties. Inhibitors of the synthesis of leukotrienesnamely, zileutonor of action of the leukotrienes at the Cys LT1 receptornamely, pranlukast, zarlukast, and montelukastameliorated laboratory-induced asthma; clinical trials were then performed demonstrating the effectiveness of this treatment compared with placebo. In these trials, antileukotrienes resulted in fewer asthma exacerbations and better lung function in patients with mild to moderate asthma than in patients treated with placebo. It is important to note, however, that, in a number of head-to-head comparisons, antileukotrienes, which have only been available for prescription for less than a decade, have not been as effective as inhaled corticosteroids for asthma control. However, the benets of oral dosing and the lack of any theoretic or known long-term toxicity make them part of the current asthma pharmacopeia. The third targeted asthma treatment is anti-IgE treatment (43). The work of multiple groups demonstrated that much of the acute asthmatic response could be attributed to activation of mast cells through cross-linking of IgE. A humanized monoclonal antibody was developed that reduced the amount of circulating free IgE, and subsequently the magnitude of clinical response elicited when patients with known specic allergies were exposed to these allergens. In the clinical trials that have led to the availability of this form of treatment, anti-IgE was shown to result in a reduction of the amount of corticosteroids required to control asthma in patients with disease severe enough to require chronic systemic steroid treatment (44). They are currently approved for use in patients with moderate to severe asthma, and their overall place in the management of asthma is still being worked out.
THE FUTURE
The benets of corticosteroids in asthma have been extensively studied; however, as noted previously, the results from the
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3. Stewart TG, Gibson GA. Asthma. In: Stedman TL, editor. Twentieth century practice: an international encyclopedia of modern medical science by leading authorities of Europe and America, Vol. VI. New York: William Wood and Co; 1896. pp. 585617. 4. Hamilton RG, Adkinson NF. Clinical laboratory assessment of IgEdependent hypersensitivity. J Allergy Clin Immunol 2003;111:S687 S701. 5. Terreehorst I, Hak E, Oosting AJ, Tempels-Pavlica Z, de Monchy JGR, Bruijnzeel-Koomen CAFM, Aalberse RC, Gerth van Wijk R. Evaluation of impermeable covers for bedding in patients with allergic rhinitis. N Engl J Med 2003;349:237246. 6. Woodcock A, Forster L, Matthews E, Martin J, Letley L, Vickers M, Britton J, Strachan D, Howarth P, Altmann D, et al., and the Medical Research Council General Practice Research Framework. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med 2003;349:225236. 7. Morgan WJ, Crain EF, Gruchalla RS, OConnor GT, Kattan M, Evans R III, Stout J, Malindzak G, Smartt E, Plaut M, et al., and the InnerCity Asthma Study Group. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004; 351:10681080. 8. Osler W, McCrae T. Bronchial asthma. In: The principles and practice of medicine, 8th ed. New York and London: D. Appleton and Co; 1914. pp. 627631. 9. Rackemann FM. Asthma. In: Cecil RL, Kennedy F, editors. A text-book of medicine, 1st ed. Philadelphia: WB Saunders; 1927. pp. 481489. 10. Rackemann FM. Asthma. In: Cecil RL, McDermott W, Wolff HG, editors. Textbook of medicine, 7th ed. Philadelphia: WB Saunders; 1947. pp. 533540. 11. Howell JBL. Asthma: acute reversible airway obstruction. In: Beeson PB, McDermott W, editors. Cecils textbook of medicine, 14th ed. Philadelphia, PA: W.B. Saunders; 1975. p. 825830. 12. Easton PA, Jadue C, Dhingra S, Anthonisen NR. A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide), given by aerosol alone or in sequence. N Engl J Med 1986;315:735739. 13. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack RM, Craig TJ, Deykin A, Fagan J, Fahy J, Fish J, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratied, randomised, placebocontrolled cross-over trial. Lancet 2004;364:15051512. 14. Rackemann FM. Asthma. In: Cecil RL, editor. Textbook of medicine, 4th ed. Philadelphia: WB Saunders; 1937. pp. 513522. 15. Rackemann FM. Asthma. In: Cecil RL, editor. Textbook of medicine, 5th ed. Philadelphia: W.B. Saunders; 1940. pp. 549558. 16. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334:13801388. 17. Melland B. The treatment of spasmodic asthma by the hypodermic injection of adrenalin. Lancet 1910;i:14071411. 18. Thomas WS. Ephedrin in asthma: a clinical report. Am J Med Sci 1926; 171:719. 19. Inman WH, Adelstein AM. Asthma mortality and pressurised aerosols. Lancet 1969;2:693. 20. Fraser PM, Speizer FE, Waters SD, Doll R, Mann NM. The circumstances preceding death from asthma in young people in 1968 to 1969. Br J Dis Chest 1971;65:7184. 21. Warrell DA, Robertson DG, Howes JN, Conolly ME, Paterson JW, Beilin LJ, Dollery CM. Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. BMJ 1970;i:6570. 22. Rossing TH, Fanta CH, Goldstein DH, Snapper JR, McFadden ER Jr. Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Respir Dis 1980;122:365371. 23. Pearlman DS, Chervinsky P, LaForce C, Seltzer JM, Southern DL, Kemp JP, Dockhorn RJ, Grossman J, Liddle RF, Yancey SW, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992;327:14201425. 24. Lemanske RF Jr, Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, Drazen JM, Chinchilli VM, Craig T, Fish JE, et al. I. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001;285:25942603. 25. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF Jr, Sorkness CA, Kraft M, Fish JE, Peters SP, Craig T, et al. I. Longacting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;285:25832593.
CAMP study highlight the inability of corticosteroids to affect long-term airway function in asthma. Studies demonstrating the remarkable benet of adding long-acting agonists to inhaled corticosteroids suggest that bronchoconstriction itself may contribute to airway remodeling in asthma (45, 46). The effects of bronchoconstriction on the airway indicate that the mechanical forces impinging on airway epithelial cells are not insignicant; they are likely up to 10-fold greater than seen during normal breathing. Such forces have been shown to activate the epidermal growth factor receptor (47), a key receptor in pulmonary biology, which is upregulated in the epithelium of asthmatic airways (48) and mediates cell proliferation, migration, and differentiation. In in vitro models of bronchoconstriction, mechanical stimulation of human airway epithelial cells elicits activation of important probrotic mediators, such as endothelin and transforming growth factor (49), and can stimulate cocultured broblasts to take on a remodeling phenotype producing collagen. Thus, recurrent mechanical stress from bronchoconstriction may contribute to the pathogenesis of airway remodeling. Such a mechanism could explain the basis for the Dutch hypothesis and is consistent with the ndings that corticosteroids do not alter the chronic progression of asthma. Dissecting the specic pathways that lead to injury in asthma will be the key to a better understanding and control of the acute and chronic manifestations of asthma. New technologies, such as gene expression proling with DNA microarrays, hold the promise to elucidation of these pathways (50). By examining the gene expression of the entire genome under different conditions, we can now investigate multiple signaling pathways in an unbiased manner. Such studies have identied novel components to asthma pathogenesis (51), such as the arginase system. The application of microarray technology to models of bronchoconstriction has identied a wide panel of mechanoresponsive genes that may contribute to alteration of the airway (52). These include a group of plasminogen activator/plasmin system genes that have well-recognized roles in extracellular matrix remodeling (53). Remarkably, plasminogen activator inhibitor-1 was also identied as an upregulated gene in a number of asthmatic models (5456). It is at the intersection of these various studies, comparing overlapping and complementary genes, that future key mediators of the asthma phenotype will likely be identied. The ultimate goal of understanding these multiple mechanistic pathways in asthma is to develop better and more effective targeted therapies. Because asthma is a syndrome, rather than a biochemical or immunologic disease, with multiple environmental and genetic determinants, it will likely require multiple types of therapy. Interrupting molecular pathways in asthma pathogenesis using new approaches, such as drugs specically targeting the epidermal growth factor receptor, arginase or plasminogen activator systems, or yet unidentied disease pathogenesis pathways, may lead to better disease control, and perhaps the reduction and elimination of the need for corticosteroids. As archaic as asthma cigarettes appear to us today, the next 100 years should bring specic asthma therapies that will make the state-of-the-art treatments we use today seem like obsolete, blunt tools from the remote past.
Conflict of Interest Statement : E.K.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript;
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