Centennial Review

AsthmaOne Hundred Years of Treatment and Onward

Eric K. Chu and Jeffrey M. Drazen

Pulmonary Division, Department of Medicine, Brigham and Women’s 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 havebeen used over the past 100 years. Belladonna alkaloids, derivedfrom the thorn-apple plant were used in 1905, and chemically syn-thesized entities in this class are still in use today. Western medicinebegan to use adrenergic stimulants approximately 100 years ago,but they were likely used in Asian medicine long before that. Sys-temic treatment with corticosteroids was introduced into the treat-ment of asthma in the mid-20th century; inhaled corticosteroidshave been in use for over 35 years. The last 40 years have alsoseen the development of the first targeted asthma treatments:cromones, antileukotrienes, and anti-IgE. As we learn more of thebiology of asthma, we anticipate that more effective targetedasthma treatments will be developed.

Keywords: adrenergic; anticholinergic; asthma; corticosteroid

Although asthma has been described as a medical entity since thetime of Aretaeus, the Cappadocian, in approximately 100 a.d.(see review by Marketos and Ballas [1]), the constellation ofphysical findings and signs that we currently recognize as asthmadates from the work of John Floyer (2) in 1698. Floyer definedasthma as “laborious respiration with lifting of the shouldersand wheezing.” He understood that asthma was intermittent andepisodic and that the treatment of asthma needs to consist ofrescue and controller therapy, termed by him as treatment “bothin fit and out of it.”

By 1900, it was well established that certain forms of asthmacould be brought on by exposure to environmental allergens. InStedman’s Twentieth Century Practice, published in 1896, SirThomas Granger Stewart and George Alexander Gibson (3)wrote about asthma:

The treatment of asthma involves the treatment of the patient duringfits and between the fits. The general indications are:

1. To allay the spasm during the paroxysm;

2. To find out and remove the exciting cause . . .

3. To treat complications and sequelae and to improve the generalhealth.

Thus, more than 100 years ago, the general approach toasthma 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 andWomen’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: jdrazen@nejm.org

Am J Respir Crit Care Med Vol 171. pp 1202–1208, 2005Originally Published in Press as DOI: 10.1164/rccm.200502-257OE on March 18, 2005Internet address: www.atsjournals.org

This article examines the evolution of the treatment of asthmaby environmental manipulation and drug treatments over thepast 100 years. Because we want to identify the most commonlyused general practices until the late 20th century, we take mostof our guidance from generally accepted textbooks of medicine.We also have tried to identify the key contributions that led tothe evolution of asthma treatment.

IDENTIFICATION OF ENVIRONMENTAL ALLERGENS

In the 1896 textbook of Stedman, as noted previously, Stewartand Gibson (3) offer advice for the management of the patientwith asthma based on removal of the offending allergens fromthe environment: “This may be the avoidance of certain foods,the avoidance of exposure to dust or pollen or flowers . . . orother specific irritants. It may be the correction of a gastric . . .disorder . . . or it may be the removal of nasal polyps.”

Although our methods of identifying allergens to whichcertain patients are hypersensitive have improved since this sum-mary more than 100 years ago, the general approach to environ-mental manipulation treatment remains the same. Before themid-1800s, relevant allergens could be identified only throughcareful history taking. Just more than 100 years ago, techniqueswere developed for skin testing to establish the diagnosis of hayfever; these were then applied to the diagnosis of allergen-drivenasthma. In the last 30 years, radioallergosorbent testing andother tests designed to identify IgE specific for a given allergenbecame available (4).

It is still somewhat controversial as to whether allergen elimi-nation leads to an improvement in asthmatic status. There havebeen recent controlled clinical trials in which selective coveringof mattresses with house–dust-mite–proof covers failed to showa benefit in asthma severity or lung function (5, 6). However,in these studies, only a single environmental intervention wasused. Another study, in which multiple environmental interven-tions were used, including covering mattresses, using high-efficiency particle-filtering vacuum cleaners, removing cigarettesmoke from the environment, and remediating other householdallergens, such as those from cockroaches and rodents, was asso-ciated with a small improvement in the number of asthma symp-tom days experienced by inner-city children (7). However, in thisstudy, objective measures of lung function were not recorded.

In summary, over the last century, we have recognized thatasthma may be precipitated by certain environmental exposuresand that eliminating these exposures may be of value in asthmatreatment. We have become more sophisticated in our methodsof identifying potentially deleterious environmental exposures,but, as many clinicians know, eliminating such exposures fromthe patient’s environment is often not easy to do.

ASTHMA PHARMACOTHERAPY

There are four general types of pharmacologic treatment thathave been used for asthma over the past 100 years. Interestingly,

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most of the treatments, once introduced, have remained in thepharmacopeia, although the specific entities and methods ofdelivery have changed. These four overlapping epochs of thepharmacologic treatment of asthma are as follows: (1) the useof anticholinergic belladonna-related alkaloids; (2) the use ofnon–anti-cholinergic bronchodilator stimulation; (3) the use ofcorticosteroids; and (4) the use of specifically targeted asthmatreatments—namely, cromones, antileukotrienes, and anti-IgE.Each of these will be considered separately.

ANTICHOLINERGIC ASTHMA TREATMENT

In Stedman’s Twentieth Century Practice of Modern MedicalScience, Stewart and Gibson (3) suggest that one of the primarytreatments for an asthmatic paroxysm was the use of belladonnaalkaloids; often these were delivered by smoking “asthma ciga-rettes” (Figure 1).

Smoking tobacco benefits a few, but the addition of a little stramo-nium to tobacco, or the smoking of cigarettes composed largely ofstramonium, is of far greater service [in the treatment of an asthmaticparoxysm]. There are many forms of cigarettes sold by the druggists.

Stramonium is the dried leaf and the flowering or fruitingtops of the plant, Datura stramonium. This is also referred toas the thorn-apple plant. The active ingredients in this werealkaloids of belladonna, which we now know had the effectof inhibiting cholinergic neurotransmission and thereby reflexbronchoconstriction.

In 1914, in the eighth edition of the Principles and Practiceof Medicine, Osler (8) points out that hypodermic injections ofpilocarpine can be effective in the treatment of asthma. Healso 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 pastillescontain some plant of the order Solanaceae . . . . Excellentcigarettes are now manufactured and asthmatics try various sortssince one form benefits one patient, another form anotherpatient.”

Thus, in 1914, anticholinergics by injection or inhalation wereconsidered as first-line asthma therapies. Osler also made theimportant observation of the intraindividual differences in theresponse to asthma treatment. We now appreciate that thesedifferences may reflect genetic variations in the mechanismsleading to the asthmatic response among subjects.

In the 1927 edition of Cecil’s A Text-book of Medicine, FrancisRackemann (9) again suggests the use of the smoke of stramo-nium leaves, atropine, and belladonna. In the seventh editionof Cecil’s A Textbook of Medicine, published in 1947, Racke-mann (10) still suggests the use of asthma powders or asthmacigarettes with the active ingredient consisting of belladonna-type alkaloids. However, by 1975, when the 14th edition of thetextbook was published, belladonna alkaloids were not consid-ered a significant enough part of asthma treatment to be includedby J.B.L. Howell (11).

The treatment of asthma with ipratropium bromide, a stableatropine-like compound, was introduced in the 1980s (12). Al-though its use in asthma rescue treatment has not been approvedby the U.S. Food and Drug Administration, it was used success-fully in a recent study sponsored by the National Institutes ofHealth Asthma Clinical Research Network (13), as an asthmarescue therapy in patients with mild intermittent asthma. Thiswas necessary because the study identified a subset of patientswith asthma who had adverse responses to adrenergic bronchodi-lators, and it was therefore necessary to manage these patientswith a nonadrenergic bronchodilator, such as ipratropiumbromide.

These data show that the use of belladonna alkaloids hasbeen advocated in the treatment of asthma for more than 100years. The mechanism of effect is not known with precision butis likely the inhibition of reflex bronchoconstriction mediatedvia cholinergic pathways.

NON–ANTI-CHOLINERGIC BRONCHODILATORS

Methyl Xanthines

Bronchodilators other than belladonna alkaloids were not men-tioned in Stedman’s 1896 textbook or in Osler’s 1914 edition ofthe Principles and Practice of Medicine; although in that latterwork, coffee is recommended as a treatment for asthma. Thereis no mention by Rackemann of the use of theophylline, orrelated compounds, in the fourth edition (published in 1937) ofCecil’s Textbook of Medicine (14), but in the fifth edition (1940),this treatment is mentioned (15): “Aminophylline in doses of0.25 Gm. dissolved in 10 cc. of water is often very effective wheninjected intravenously.” From that time forward into the present,methyl xanthines have been used, most often in the form oftheophylline or the water-soluble, related compound aminophyl-line, for the treatment of asthma. Although the mechanism ofaction of these agents is not established with certainty, they arebronchodilators by virtue of their ability to inhibit phosphodies-terase and thus to inhibit the breakdown of cyclic AMP. How-ever, they have many other potential mechanisms of action inasthma, and a full review of their use in asthma is beyond thescope of this article; readers are referred to authoritative reviewsby others (16).

Theophylline continues to be an inexpensive and effectiveasthma treatment. However, it has a low ratio of therapeuticbenefit to potentially toxic side effects. Dosing needs to be care-fully monitored to be sure that a given patient is receiving thebenefits of treatment without its side effects. To complicate mat-ters, theophylline metabolism varies substantially both amongindividuals and in a given subject. Even when an effective doseis established, it is important to continue to monitor plasma druglevels. Given these difficulties, many consider that theophyllineis not a first-line asthma therapy.

Direct Adrenergic Bronchodilators

Direct adrenergic bronchodilators were introduced in Westernmedicine for the treatment of asthmatic attacks in the early1900s. In an article in the Lancet in 1910, Melland (17) describeddramatic responses to adrenaline injection in three patients withasthma who were unresponsive to usual asthma treatment. In1926, Thomas (18) described the use of ephedrine in asthma,but it is highly likely that this treatment had already been usedin China for centuries. When the seventh edition of Cecil’s Text-book of Medicine was published, Rackemann (9) wrote,

The treatment of an attack is usually simple. Adrenalin chlorideinjected subcutaneously can control almost any attack from a timevarying from minutes to hours. The dose of 0.25 c.c. of a 1:1000solution often works as well as 1.0 c.c. The dose can be repeated athalf-hour intervals if necessary.

In the 1947 edition, Rackemann (10) amended this statementto suggest that epinephrine could be given by inhalation of a1:100 solution to relieve asthmatic bronchoconstriction (Figure2). By the mid-1950s, metered-dose inhalers had been devisedfor the delivery of epinephrine and isoproterenol, the latter beinga relatively specific �-adrenergic agonist. These inhalers werewidely used for asthma treatment; they are still in use today,even though there are bronchodilators available with fewer sideeffects.

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Figure 1. Asthma cigarettes were used to deliveralkaloids with bronchodilator properties. Theywere sold commercially for asthma treatmentuntil just before the middle of the 20th century.(Courtesy of Mark Saunders and his “Inhala-torium,” www.inhalatorium.com.)

However, there were significant adverse effects associatedwith this treatment. There was an epidemic of asthma deathsthat occurred in Britain during the mid-20th century. Analysisof epidemiologic data suggested that this epidemic was associ-ated with the widespread use of isoproterenol forte—a high-strength isoproterenol solution packaged in the metered-doseinhaler (19, 20). The epidemic abated when the high potencyinhaler was withdrawn from the market and a physician educa-tion campaign to be sure that patients with asthma were ade-quately treated was launched. Because the actions were takentogether, it is impossible to know with confidence which wasresponsible for the improved outcomes.

Figure 2. The use of inhaled adrenaline to treatasthma began in the first third of the 20th centuryand continues to this day. The images show anearly nebulizer marketed for the treatment ofasthma. (Courtesy of Mark Saunders and his “In-halatorium,” www.inhalatorium.com.)

In the 1960s and 1970s, relatively specific �2-adrenergic ago-nists were developed for use by inhalation (21). Albuterol(known outside the United States as salbutamol), metaprotere-nol, isoetherine, terbutaline, and others were introduced into themarketplace. These agents had rapid onset of action, producedbronchodilation lasting 4 to 6 hours, and became the “bronchodi-lator of choice.” Since the mid-1980s, bronchoconstriction thatcould be relieved by the inhalation of a specific �2 agonist wascommonly included as a diagnostic criterion of asthma. Rossingand others (22) showed that inhalation of selective �2 agonistswas equally, if not more, effective than injection of subcutaneousepinephrine for the relief of the airway obstruction associatedwith acute asthma attacks. Eventually this led to the widespread

Centennial Review 1205

use of inhaled selective �2 bronchodilators as the primary treat-ment of acute asthmatic airway obstruction.

The adrenergic bronchodilator armamentarium has advancedwith the development of selective �2 agonists that were engi-neered to provide a long duration of bronchodilator activity.Long-acting bronchodilators, such as fenoterol, formoterol, andsalmeterol, were introduced into the marketplace worldwide foruse in the control of asthma symptoms (23). These agents areeffective bronchodilators, but a number of studies have shownthat they should not be used as the sole agents for the treatmentof asthma, but rather should be used in a coordinated programof asthma medications, which includes agents such as inhaledcorticosteroids or leukotriene antagonists (24, 25).

In the past 4 years, there have been data available to sug-gest that a proportion of patients who regularly use selective�2-adrenergic agonists, such as albuterol, may develop residualbronchoconstriction many hours after the acute bronchodilatoreffect of the medication has worn off. Findings from retrospec-tive analyses (26, 27) and a double-blind, randomized, placebo-controlled, genotype-stratified crossover trial indicate thatpatients possessing the Arg-Arg genotype, at position 16 of the�2-adrenergic receptor, are at risk for developing this residualbronchoconstriction (13). Not only is this manifested by lowerflow rates but patients with this genotype had increased asthmasymptoms and increased asthma medication use during the pe-riod of regular treatment with albuterol, compared with placeboin patients harboring the Arg-Arg genotype as well as comparedwith patients with the GLY-GLY genotype at position 16 of the�2-adrenergic receptor. Although these data need to be repli-cated in a larger trial powered on asthma exacerbations, it makessense to consider alternative asthma action plans for patientswho appear to develop adverse effects when treated with �2-adrenergic agonists on a regular basis.

CORTICOSTEROIDS

Corticosteroids were not generally available for medicinal useuntil the late 1940s. In the early 1950s, anecdotal case reportsshowed that treatment with adrenal corticotropic hormone orcorticosteroids resulted in an improvement in asthma. For exam-ple, McCombs (28) described five cases of asthma refractoryto treatment with standard therapy that had a significant re-sponse to systemic treatment with corticosteroids or adrenalcorticotropic hormone (Figure 3). He wrote, “There is no doubtthat in the five cases herein reported corticotropin and cortisonebrought about changes that could not have been produced soregularly by any other known method of treatment.” By the1970s, systemic corticosteroids had been accepted as the standardtherapy to both treat and prevent asthma exacerbations. For

Figure 3. A pictorial description of Case 3as reported by McCombs (28). The heightof the smooth curved line denotes asthmaseverity, whereas the height of the bars de-notes the number of milligrams of cortisoneor units of adrenal corticotropic hormone(ACTH) used in treatment. Redrawn and re-printed by permission from Reference 28.

patients with severe asthma, either the use of daily or every-other-day oral corticosteroids was considered state-of-the-arttherapy. The major issues were how to treat asthma in patientswith disease of moderate severity without encumbering the se-vere side effects associated with daily corticosteroid therapy.

The solution to this problem came in the form of inhaledcorticosteroids. Brown and colleagues (29) reported that patientswho were dependent on oral corticosteroids could be switchedto inhaled corticosteroids (Figure 4). Later, a large trial orga-nized by the British Thoracic Society showed that steroid-naivepatients with moderate to severe asthma could be controlledwith this treatment (30). Although these studies were widelyconfirmed (31, 32), physicians and patients were slow to adopttheir use, perhaps because their effects on the airways weredelayed compared with those achieved with bronchodilators.However, over time, it became clear that they were effectiveasthma treatments and safe relative to the use of systemiccorticosteroids.

The study that had the biggest impact on the use of inhaledcorticosteroids was that of Haahtela and coworkers (33). Inthis trial, patients with newly diagnosed asthma were randomlyassigned to receive inhaled corticosteroids or an inhaled �2 ago-nist as their primary asthma treatment for 2 years. Over theperiod of the trial, there was less bronchial responsiveness amongthe patients treated with inhaled corticosteroids than there wasamong the patients treated with terbutaline. In a follow-up study,patients who had been assigned to terbutaline were assigned tocorticosteroids and experienced a smaller degree of improve-ment than those who had started on corticosteroids, suggestingthat treatment early on was more effective than treatment laterinto the course of asthma (34).

However, this study was not designed to directly test thecritical question: Would the regular use of inhaled corticosteroidsmodify the long-term effects of asthma? There have been twolarge long-term studies that have been designed to do so. Inthe Childhood Asthma Management Program (CAMP) study,children, aged 7 to 12 years at onset, were assigned to treatmentwith inhaled corticosteroids, nedocromil, or placebo on a dailybasis (35). There were no differences over the 5 years of studywith respect to the rate of loss of lung function between thegroups, whereas there were differences, in favor of inhaled bude-sonide, in the time to first asthma exacerbation. These dataindicated that corticosteroids were effective at preventing asthmaparoxysms but did not modify the underlying loss of lung func-tion associated with chronic asthma. In a double-blind, random-ized, placebo-controlled trial, adults and children with newlydiagnosed asthma were assigned to treatment with inhaled bude-sonide or placebo (36). As in the CAMP trial, there were fewer

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Figure 4. Case example of the effectiveness of inhaled corticosteroidsfrom the original report of Brown and coworkers (Reprinted by permis-sion from Reference 29). The case legend from Brown and coworkersreads as follows: “Man aged 45. Late onset asthma-allergens unknown.A good example of the usefulness of aerosol therapy until airways clearedby high-dosage corticosteroids. Disodium cromoglycate (DSCG) hadbeen used for a year but was no longer effective. High level [of function]maintained to date on aerosol alone. The aerosol actually caused bron-chospasm when first introduced.”

asthma exacerbations in the group assigned to budesonide. Therewas an overall 0.88% improvement, in lung function expressedas a percentage of predicted value, over time in favor of budeson-ide, but the effects were not consistent over age groups, raisingquestions as to the robustness of the findings.

Inhaled corticosteroids have side effects. When used on aregular basis for long periods of time, there are documentedadverse effects, such as loss of stature (35, 36), decreased bonemineralization, glaucoma, and cataracts (37–39). Inhaled cortico-steroids have been recommended and used in the treatment ofasthma for just over 30 years; they are very effective as “asthma-controller” therapies, but there are no convincing data that theyare disease-modifying treatments.

SPECIFICALLY TARGETED ASTHMA TREATMENTS

After 1960, substantial research efforts were put into understand-ing the pathobiology of asthma. Three specifically targetedasthma treatments have emerged from this research effort. Thefirst was disodium cromoglycate; the story of its discovery is ofinterest in light of the current environment for clinical research.The drug’s discoverer was a physician named Roger Altounyan(1922–1987), who had a very clear asthmatic response to inhaledguinea pig dander. Altounyan was convinced of the antiasthmaticproperties of certain folk remedies. As a researcher and em-ployee of a small drug company, he worked with chemists toextract potentially active ingredients from natural products andtested these by administering them to himself before exposinghimself by inhalation to extracts of guinea pig dander. Usingthis process as his “discovery model,” he identified disodium

cromoglycate, which was eventually marketed as an antiasthma-tic drug. Both it and another drug in the same family, nedocromilsodium, are available as asthma treatments (40, 41) but are usedmost frequently in children.

Although these agents were discovered by searching for drugswith antiasthmatic effects, and in that sense are targeted treat-ments, their exact mechanism of “antiallergic” action is notknown with certainty. In contrast, antileukotriene and anti-IgEtreatments for asthma were developed to target specific knownpathobiologies of asthma. The antileukotrienes were developedto block the potent biological bronchoconstrictor, previouslyknown as slow-reacting substance of anaphylaxis, or SRS-A, andnow appreciated to be a mixture of the acidic lipids, leukotrienes,C4, D4, and E4 (42). The role of these substances in asthmaseemed reasonable because they are released by mast cellsduring anaphylactic reactions and because of their potent bron-choconstrictor properties. Inhibitors of the synthesis of leuko-trienes—namely, zileuton—or of action of the leukotrienes atthe Cys LT1 receptor—namely, pranlukast, zafirlukast, and mon-telukast—ameliorated laboratory-induced asthma; clinical trialswere then performed demonstrating the effectiveness of thistreatment compared with placebo. In these trials, antileuko-trienes resulted in fewer asthma exacerbations and better lungfunction in patients with mild to moderate asthma than in pa-tients 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 adecade, have not been as effective as inhaled corticosteroids forasthma control. However, the benefits of oral dosing and thelack of any theoretic or known long-term toxicity make thempart of the current asthma pharmacopeia.

The third targeted asthma treatment is anti-IgE treatment(43). The work of multiple groups demonstrated that much ofthe acute asthmatic response could be attributed to activationof mast cells through cross-linking of IgE. A humanized mono-clonal antibody was developed that reduced the amount of circu-lating free IgE, and subsequently the magnitude of clinicalresponse elicited when patients with known specific allergieswere exposed to these allergens.

In the clinical trials that have led to the availability of thisform of treatment, anti-IgE was shown to result in a reductionof the amount of corticosteroids required to control asthma inpatients with disease severe enough to require chronic systemicsteroid treatment (44). They are currently approved for use inpatients with moderate to severe asthma, and their overall placein the management of asthma is still being worked out.

CHANGING THE TREATMENT PARADIGMS

Among our current asthma treatments, bronchodilators derivetheir effect from diminished smooth muscle constriction. It hasbeen assumed that corticosteroids are effective in preventingasthmatic exacerbations by diminishing the inflammatory com-ponent of asthma, but the precise nature of this inflammatorycomponent and how the corticosteroids affect this response is notyet known. As we move into the future, it would be worthwhile toconsider the role of inflammation and bronchoconstriction inasthmatic events. This is especially important in light of theso-called Dutch hypothesis, which suggests that patients withrecurrent airway constriction are those who may go on to developchronic airway obstruction.

THE FUTURE

The benefits of corticosteroids in asthma have been extensivelystudied; however, as noted previously, the results from the

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CAMP study highlight the inability of corticosteroids to affectlong-term airway function in asthma. Studies demonstratingthe remarkable benefit of adding long-acting � agonists to in-haled corticosteroids suggest that bronchoconstriction itself maycontribute to airway remodeling in asthma (45, 46). The effects ofbronchoconstriction on the airway indicate that the mechanicalforces impinging on airway epithelial cells are not insignificant;they are likely up to 10-fold greater than seen during normalbreathing. Such forces have been shown to activate the epidermalgrowth 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 stimula-tion of human airway epithelial cells elicits activation of impor-tant profibrotic mediators, such as endothelin and transforminggrowth factor � (49), and can stimulate cocultured fibroblaststo take on a “remodeling” phenotype producing collagen. Thus,recurrent mechanical stress from bronchoconstriction may con-tribute to the pathogenesis of airway remodeling. Such a mecha-nism could explain the basis for the Dutch hypothesis and isconsistent with the findings that corticosteroids do not alter thechronic progression of asthma.

Dissecting the specific pathways that lead to injury in asthmawill be the key to a better understanding and control of theacute and chronic manifestations of asthma. New technologies,such as gene expression profiling with DNA microarrays, holdthe promise to elucidation of these pathways (50). By examiningthe gene expression of the entire genome under different condi-tions, we can now investigate multiple signaling pathways in anunbiased manner. Such studies have identified novel componentsto asthma pathogenesis (51), such as the arginase system. Theapplication of microarray technology to models of bronchocon-striction has identified a wide panel of mechanoresponsive genesthat may contribute to alteration of the airway (52). These in-clude a group of plasminogen activator/plasmin system genesthat have well-recognized roles in extracellular matrix remodel-ing (53). Remarkably, plasminogen activator inhibitor-1 was alsoidentified as an upregulated gene in a number of asthmatic mod-els (54–56). It is at the intersection of these various studies,comparing overlapping and complementary genes, that futurekey mediators of the asthma phenotype will likely be identified.

The ultimate goal of understanding these multiple mechanis-tic pathways in asthma is to develop better and more effectivetargeted therapies. Because asthma is a syndrome, rather thana biochemical or immunologic disease, with multiple environ-mental and genetic determinants, it will likely require multipletypes of therapy. Interrupting molecular pathways in asthmapathogenesis using new approaches, such as drugs specificallytargeting the epidermal growth factor receptor, arginase or plas-minogen activator systems, or yet unidentified disease pathogen-esis pathways, may lead to better disease control, and perhapsthe reduction and elimination of the need for corticosteroids.As archaic as “asthma cigarettes” appear to us today, the next100 years should bring specific asthma therapies that will makethe 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 witha 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 interestin the subject of this manuscript;

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