New Treatments For Asthma Research Articles

Myricetin ameliorates airway inflammation and remodeling in asthma by activating Sirt1 to regulate the JNK/Smad3 pathway

BackgroundMyricetin has various biological activities and health benefits; however, its effects on airway remodeling in asthma have not been reported. PurposeWe aimed to investigate the possibility that myricetin improves airway remodeling by activating Sirt1 and has potential as a new treatment for asthma. MethodsRAW 264.7 cells were stimulated with lipopolysaccharide and co-cultured with 3T6 cells in vitro to simulate the in vivo effects of inflammation on airway remodeling. Using an ovalbumin-induced chronic asthma mouse model, we compared changes in inflammatory factors and airway remodeling-related factors under treatment with myricetin and/or the Sirt1 inhibitor EX-527 using western blotting and quantitative PCR. Expression plasmids carrying Smad3 site mutations were transfected into 3T6 cells to identify the Sirt1 deacetylation site on Smad3 protein. ResultsMyricetin significantly reduced the infiltration of airway inflammatory cells and the production of interleukin (IL)-6 and IL-5, and inhibited mucus secretion by goblet cells, collagen fiber proliferation, and the increase in inflammatory cells in bronchoalveolar lavage fluid from asthmatic mice. Results of in vitro experiments were consistent with those conducted in vivo. Exploring the mechanism of action of myricetin, we found that myricetin downregulated the levels of phosphorylated (p)-JNK, p-Smad3, and acetylated Smad3 proteins by activating Sirt1 both in vivo and in vitro. K341 was identified as the main deacetylation site of Smad3 by myricetin-activated Sirt1. ConclusionMyricetin ameliorates airway inflammation and remodeling in asthma by activating Sirt1 to regulate the JNK/Smad3 pathway.

Tailored Biologics Selection in Severe Asthma.

The management of severe asthma presents a significant challenge in asthma treatment. Over the past few decades, remarkable progress has been made in developing new treatments for severe asthma, primarily in the form of biological agents. These advances have been made possible through a deeper understanding of the underlying pathogenesis of asthma. Most biological agents focus on targeting specific inflammatory pathways known as type 2 inflammation. However, recent developments have introduced a new agent targeting upstream alarmin signaling pathways. This opens up new possibilities, and it is anticipated that additional therapeutic agents targeting various pathways will be developed in the future. Despite this recent progress, the mainstay of asthma treatment has long been inhalers. As a result, the guidelines for the appropriate use of biological agents are not yet firmly established. In this review, we aim to emphasize the current state of biological therapy for severe asthma and provide insights into its future prospects.

C-FLIP protects eosinophils from TNF-α-mediated cell death in vivo.

Understanding the signals that regulate eosinophil survival and death is critical to developing new treatments for asthma, atopy, and gastrointestinal disease. Previous studies suggest that TNF-α stimulation protects eosinophils from apoptosis, and this TNF-α-mediated protection is mediated by the upregulation of an unknown protein by NF-κB. Here, we show for the first time that eosinophils express the caspase 8-inhibitory protein c-FLIP, and c-FLIP expression is upregulated upon TNF-α stimulation. Considering that c-FLIP expression is regulated by NF-κB, we hypothesized that c-FLIP might serve as the “molecular switch” that converts TNFRI activation to a pro-survival signal in eosinophils. Indeed, we found that one c-FLIP isoform, c-FLIPL, is required for mouse eosinophil survival in the presence of TNF-α both in vitro and in vivo. Importantly, our results suggest c-FLIP as a potential therapeutic target for the treatment of eosinophil-mediated disease.

Inhibition of the early asthmatic response to inhaled allergen by the 5-lipoxygenase activating protein inhibitor GSK2190915: a dose–response study

BackgroundGSK2190915, a 5-lipoxygenase activating protein inhibitor, inhibits the production of cysteinyl leukotrienes and leukotriene B4 and 5-oxo-6,8,11,14-eicosatetraenoic acid. We have previously reported that GSK2190915 100 mg daily inhibits early and late asthmatic responses to inhaled allergen; the effects of lower doses have not been reported. This study assessed the dose–response effects of GSK2190915 10 mg and 50 mg on the early asthmatic response (EAR) to inhaled allergen.MethodsNineteen subjects with mild asthma and an EAR were enrolled in a randomized, double-blind, three-way crossover study of GSK2190915 10 mg, 50 mg, and placebo orally once-daily for 3 days. Allergen challenge was performed 2 hours after the third dose.ResultsCompared with placebo, GSK2190915 10 mg and 50 mg caused significant, dose-dependent attenuation of the minimum forced expiratory volume at 1 second (FEV1) absolute change from baseline; mean treatment differences were 0.21 L (95% confidence interval [CI] 0.04 L, 0.38 L) and 0.41 L (95% CI 0.24 L, 0.58 L), respectively. GSK2190915 50 mg was more effective than 10 mg; mean difference between treatments was 0.20 L, (95% CI 0.03 L, 0.36 L). Compared with placebo, GSK2190915 50 mg, but not 10 mg, significantly inhibited the weighted mean FEV1 absolute change from baseline.ConclusionGSK2190915 50 mg attenuated the EAR similarly to GSK2190915 100 mg in our previous study, suggesting 50 mg is at the top of the dose–response curve. GSK2190915 10 mg is a suboptimal dose. The EAR can be used to assess the therapeutic dose of a new treatment for asthma.

TH2, allergy and group 2 innate lymphoid cells

The initiation of type 2 immune responses by the epithelial cell-derived cytokines IL-25, IL-33 and TSLP has been an area of extensive research in the past decade. Such studies have led to the identification of a new innate lymphoid subset that produces the canonical type 2 cytokines IL-5, IL-9 and IL-13 in response to IL-25 and IL-33. These group 2 or type 2 innate lymphoid cells (ILC2 cells) represent a critical source of type 2 cytokines in vivo and serve an important role in orchestrating the type 2 response to helminths and allergens. Further characterization of ILC2 cell biology will enhance the understanding of type 2 responses and may identify new treatments for asthma, allergies and parasitic infections. Interactions between ILC2 cells and the adaptive immune system, as well as examination of potential roles for ILC2 cells in the maintenance of homeostasis, promise to be particularly fruitful areas of future research.

189 Efficacy and Safety of Two Doses of Mometasone Furoate/Formoterol Combination Treatment in Subjects With Severe Asthma

BackgroundMultiple strengths of mometasone furoate/formoterol (MF/F) metered-dose inhaler combination therapy have been investigated as new treatments for asthma. We report efficacy/safety findings from an MF/F study in subjects with severe asthma previously uncontrolled on high-dose inhaled corticosteroids (ICS) with or without a long-acting ß2-agonist (LABA).MethodsThis was a 3-month, randomized, double-blind, parallel-group, multicenter study with a 2- to 3-week open-label run-in period during which subjects received mometasone furoate (MF) 400 μg twice daily (BID). Subjects (≥12 years) were randomized to MF/F 200/10 μg BID, MF/F 400/10 μg BID, or MF 400 μg BID. The primary endpoint was the area under the curve (AUC) of the change in serial (0−12 hours) forced expiratory volume in 1 second (FEV1) for MF/F 400/10 μg vs MF 400 μg from baseline to week 12. Adverse events (AEs) and other clinical safety measures were recorded.Results728 subjects were randomized (mean: age, 47.9 years; asthma duration, 14.0 years; FEV1 % predicted, 66.3; reversibility, 22.9%; Asthma Control Questionnaire score, 1.93). Improvements in mean changes from baseline in FEV1 AUC0−12h at week 12 were: MF/F 200/10 μg = 3.59 L × h; MF/F 400/10 μg = 4.19 L × h; MF 400 μg = 2.04 L × h, with both MF/F doses significantly better than MF (P < 0.001). These FEV1 AUC0–12h values with MF/F 200/10 μg, MF/F 400/10 μg, and MF 400 μg correspond to average hourly increases of 0.30, 0.35, and 0.17 L, respectively. MF/F was associated with a rapid (<5 minutes) and sustained improvement in lung function. The percentages of subjects experiencing an asthma deterioration (ie, severe asthma exacerbation) were 12.4% (MF/F 200/10 μg), 12.2% (MF/F 400/10 μg), and 18.3% (MF 400 μg). There were no notable differences in AEs between the groups.ConclusionsBoth the 200/10 μg BID and 400/10 μg BID doses of MF/F combination therapy led to significantly greater improvements in lung function compared with 400 μg BID MF monotherapy in subjects with severe asthma previously treated with an ICS alone or in combination with LABA.

Asthma burden in the United States: Results of the 2009 Asthma Insight and Management survey

Updated guidelines and new treatments for asthma have become available since the last major survey of asthma management in the United States was completed ∼11 years ago. The Asthma Insight and Management (AIM) survey was conducted to assess the current status of asthma burden in the United States. A geographically stratified screening of 60,682 households provided a national sample of 2500 patients with current asthma (2186 adults aged ≥18 years; 314 adolescents aged 12-17 years). A national sample of 1004 adults without current asthma was interviewed for comparison with the adult asthma population, and 309 asthma health care providers were surveyed for their opinions about the burden of asthma. Asthma prevalence in the United States was estimated at 8%. Twice as many adult asthma patients rated their health as "only fair," "poor," or "very poor," or experienced limitations in activity because of health problems, compared with the general population. Asthma also frequently caused negative emotional symptoms in patients. Most patients experienced asthma throughout the year (63%) and symptoms within the 4 weeks before the summer survey (68%). Overall, 41% of patients responded that asthma interfered with their/their child's life "some" or "a lot". During the year before the survey, 69% of patients experienced at least one severe asthma episode. Asthma burden in the United States remains high despite the availability of updated treatment guidelines and new therapies. Asthma care in the United States remains suboptimal, indicating the need for continued improvements in patient management.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles

Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague–Dawley rats

Hypocapnia and hypercapnia constrict and relax airway smooth muscle, respectively, through pH- and calcium (Ca(2+))-mediated mechanisms. In this study we explore a potential role for the airway epithelium in these responses to carbon dioxide (CO(2)). Contractile and relaxant responses of isolated rat bronchial rings were measured under hypocapnic, eucapnic, and hypercapnic conditions. Substance P was added to methacholine precontracted bronchial rings with and without epithelium. The role of Ca(2+) was assessed using Ca(2+)-free solutions and a Ca(2+) channel blocker, nifedipine. The effects of pH were assessed in solutions with HEPES buffer. Hypocapnic challenge increased the organ bath's pH and increased bronchial smooth muscle resting tension. This effect was abolished with HEPES buffer and partially inhibited by nifedipine. Hypocapnic conditions suppressed substance P-induced epithelium-dependent relaxation, whereas hypercapnia augmented the response. The epithelial hypocapnic effect was pH dependent, whereas the hypercapnic effect was pH independent. CO(2) had no effect on the epithelial independent smooth muscle agonists methacholine and isoproterenol. In conclusion our data indicate that, in addition to the effects of pH and Ca(2+), CO(2) affects airway smooth muscle by a pH-independent, epithelium-mediated mechanism. These findings could potentially lead to new treatments for asthma involving CO(2)-sensing receptors in the airways.

Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses

Because they can recognize and sample inhaled allergens, dendritic cells (DC) have been shown to be responsible for the initiation and maintenance of adaptive Th2 responses in asthma. It is increasingly clear that DC functions are strongly influenced by a crosstalk with neighboring cells like epithelial cells. Whereas the epithelium was initially considered only as a barrier, it is now seen as a central player in controlling the function of lung DCs through release of innate cytokines-promoting Th2 responses. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DC. A better understanding of these interactions might lead to a better prevention and ultimately to new treatments for asthma.

Statin drugs, metabolic pathways, and asthma: a therapeutic opportunity needing further research.

The chance discovery of hydroxymethylglutaryl (HMG)-CoA reductase inhibitors has revolutionized the care of patients with cardiovascular disease. The unexpected finding that these cholesterol-lowering drugs (or 'statins') also possess pleiotropic immunomodulatory properties, has opened a new area of research which investigates the anti-inflammatory and anti-proliferative properties of statins. In this brief commentary, we discuss the potential application of these drugs in asthma, where metabolic pathways pertinent to lung inflammation, in addition to the mevalonate cascade, may be targeted. We review mechanisms of action, discuss the potential therapeutic use of statins in asthma, share some preliminary data from our laboratory, discuss results from recent clinical trials in asthma, and propose a new target asthma subpopulation that could potentially benefit. We conclude our essay by highlighting the mevalonate-dependent and -independent pathways that may be modulated by statins, including the emerging area of cholesterol, sphingolipid, and lipid raft biology in lung disease. In this is an opportunity to develop new treatments for asthma, where innovative therapies are urgently needed to prevent acute exacerbations and alter disease progression.

Efficacy and safety of medium and high doses of mometasone furoate/formoterol (MF/F) combination treatment in subjects with severe persistent asthma

Background Multiple strengths of mometasone furoate/formoterol (MF/F) MDI combination therapy are under investigation as new treatments for asthma. We report efficacy/ safety findings from a 3-month MF/F study in subjects with severe asthma. Materials and methods This was a 3-month, randomized, double-blind, parallelgroup, multicenter study with a 2-3-week open-label, run-in period of mometasone furoate (MF) 400 μg twice-daily (BID). Subjects (≥12 years) were randomized to MF/F (200/10 μg or 400/10 μg BID) or MF (400 μg BID). The primary endpoint was the area under the curve (AUC) of the change in serial FEV1 (0-12 hours) for MF/F 400/10 μg vs MF 400 μg from baseline to Week 12. Adverse events (AEs) and other clinical safety measures were recorded. Results A total of 728 subjects (mean: age = 47.9 y, asthma duration = 14.0 y, FEV1 % predicted = 66.3, reversibility = 22.9%, Asthma Control Questionnaire [ACQ] score = 1.93) were randomized. Improvements in mean changes from baseline in FEV1 AUC0-12 h (L ×h ) at Week 12 were MF/F 200/10 μg = 3.59, MF/F 400/10 μg = 4.19, and MF 400 μg = 2.04, with both MF/F doses significantly better than MF (p < 0.001). These FEV1s correspond to average hourly increases of 0.30, 0.35, and 0.17 L, respectively. MF/F was associated with rapid (<5 min) and sustained improvement in lung function. The percentage of subjects experiencing asthma deterioration (ie, severe asthma exacerbation) was 12.4% (MF/F 200/10 μg), 12.2% (MF/F 400/10 μg), and 18.3% (MF 400 μg). There were no notable differences in AEs between the groups. Conclusions Both medium- and high-dose MF/F combination therapy led to significantly greater improvements in lung function compared with high-dose MF monotherapy in severe asthmatics.

Efficacy and Safety of Medium and High Doses of Mometasone Furoate/Formoterol (MF/F) Combination Treatment in Subjects with Severe Persistent Asthma

RATIONALE: Multiple strengths of mometasone furoate/formoterol (MF/F) MDI combination therapy are under investigation as new treatments for asthma. We report efficacy/safety findings from a 3-month MF/F study in subjects with severe asthma.

The Effects of Current Therapies on Airway Remodeling in Asthma and New Possibilities for Treatment and Prevention

Airway inflammation, airway remodeling and airway hyperresponsiveness are the fundamental components of pathogenesis that lead to symptoms and lung function changes in asthma. Airway remodeling describes the structural changes to the airways in asthma. The remodeling process involves diverse pathological changes including epithelial metaplasia, subepithelial fibrosis, angiogenesis and smooth muscle thickening. Airway remodeling contributes to irreversible loss of lung function and airway hyperresponsiveness. Remodeling is associated with severe and persistent disease but can also occur early in the course of disease pathogenesis and does not resolve spontaneously. Current asthma therapies, for example corticosteroids, are successful in treating allergic inflammation, an important factor contributing to remodeling, but do not specifically target the remodeling process, and remodeling changes progress despite optimal control of inflammation. Moreover, airway remodeling is not eradicated or prevented despite widespread use of antiinflammatory treatments. There is limited evidence for the effectiveness of leukotriene inhibitors, phosphodiesterase inhibitors, mast cell tryptase inhibitors, and peroxisome proliferator-activated receptor γ agonists in the treatment or prevention of remodeling changes. The search for novel therapies that can specifically reverse or prevent airway remodeling is an active area of research. Treatments that may be useful in preventing airway remodeling include those that directly or indirectly target single or multiple components of the airway remodeling process. Identification of novel asthma genes may also allow disease targeting. A better understanding of airway remodeling in asthma will facilitate the development of new treatments for asthma beyond control of symptoms and inflammation.

The Effects of Current Therapies on Airway Remodeling in Asthma and New Possibilities for Treatment and Prevention

Airway inflammation, airway remodeling and airway hyperresponsiveness are the fundamental components of pathogenesis that lead to symptoms and lung function changes in asthma. Airway remodeling describes the structural changes to the airways in asthma. The remodeling process involves diverse pathological changes including epithelial metaplasia, subepithelial fibrosis, angiogenesis and smooth muscle thickening. Airway remodeling contributes to irreversible loss of lung function and airway hyperresponsiveness. Remodeling is associated with severe and persistent disease but can also occur early in the course of disease pathogenesis and does not resolve spontaneously. Current asthma therapies, for example corticosteroids, are successful in treating allergic inflammation, an important factor contributing to remodeling, but do not specifically target the remodeling process, and remodeling changes progress despite optimal control of inflammation. Moreover, airway remodeling is not eradicated or prevented despite widespread use of anti-inflammatory treatments. There is limited evidence for the effectiveness of leukotriene inhibitors, phosphodiesterase inhibitors, mast cell tryptase inhibitors, and peroxisome proliferator-activated receptor gamma agonists in the treatment or prevention of remodeling changes. The search for novel therapies that can specifically reverse or prevent airway remodeling is an active area of research. Treatments that may be useful in preventing airway remodeling include those that directly or indirectly target single or multiple components of the airway remodeling process. Identification of novel asthma genes may also allow disease targeting. A better understanding of airway remodeling in asthma will facilitate the development of new treatments for asthma beyond control of symptoms and inflammation.

Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients

Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory. To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations. Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD20FEV1]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge. A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD20FEV1, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR. Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.

The role of dendritic cells in asthma.

The central importance of respiratory tract dendritic cells in the regulation of adaptive immune responses to inhaled antigens is now well established. Dendritic cells are not merely a conduit for the transfer of antigen to regional lymph nodes, but rather function as a sophisticated information transfer system linking the airway micro-environment to the adaptive immune system. Evidence from both animal models and clinical studies points to a critical role for dendritic cells in both allergic sensitization and the pathogenesis of chronic airway inflammation. This article reviews recent information on the distribution and function of dendritic cells in healthy individuals, the responsiveness of these cells to external stimuli, and the factors regulating their activation and turnover within the lung. Animal models of allergic airway inflammation continue to shed new light on the role of lung dendritic cells in T helper 1/T helper 2 switching, and the ability of these cells to direct regulatory T-cell development and immune tolerance. Recent studies have further characterized circulating dendritic cell populations, highlighting important functional differences between dendritic cells from atopic and nonatopic individuals, and have delineated the involvement of these cells in the late phase response to inhaled allergen. Because of the immunoregulatory properties of dendritic cells, the future is likely to see a concerted effort to further define the role that these cells play in allergic sensitization, as a basis for the development of new treatments for asthma and other atopic disorders.

In vitro metabolism of 2-acetylbenzothiophene: relevance to zileuton hepatotoxicity.

Zileuton, an inhibitor of 5-lipooxygenase, the initial enzyme in the leukotriene pathway, was marketed as a new treatment for asthma. This drug has been associated with liver toxicity, which has limited its clinical usefulness. We provide evidence here that the liver toxicity likely involves a sequence of biotransformations leading to 2-acetylbenzothiophene (2-ABT), which is subsequently metabolized to give a reactive intermediate(s). In vitro experiments with the human lymphoblast MCL5 cell line demonstrated that 2-ABT is cytotoxic in a P450-dependent manner. Human liver microsome (HLM) incubations with 2-ABT revealed the formation of two short-lived oxidized species, "M + 16" and "M + 32". Both of these metabolites formed adducts in the presence of GSH or NAC. Singly oxidized M + 16 adducts, from either GSH or NAC, appeared to be unstable in acidic medium and eliminated water readily to form a new compound. Authentic synthetic standards demonstrated that 2-ABT-S-oxide M1 corresponded to the M + 16 metabolite and that the S-oxide underwent nucleophilic addition with GSH and NAC to produce the singly oxidized adducts observed in HLM. The S-oxide adducts readily eliminated water to form a rearomatized 2-ABT-GSH adduct or 2-ABT-NAC adduct. Coelution experiments with the synthetic standard confirmed the structure of the eliminated 2-ABT-NAC adduct C1. LC/MS analyses of urine samples collected from rats dosed with zileuton indicate that C1 is a metabolite of zileuton formed in vivo. The in vitro and in vivo data presented here demonstrate the formation of 2-ABT from zileuton and its further bioactivation to a potentially toxic metabolite.

The role of RhoA-mediated Ca2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness

Smooth muscle contraction is mediated by Ca2+-dependent and Ca2+-independent pathways. The latter Ca2+-independent pathway, termed Ca2+ sensitization, is mainly regulated by a monomeric GTP binding protein RhoA and its downstream target Rho-kinase. Recent studies suggest a possible involvement of augmented RhoA/Rho-kinase signaling in the elevated smooth muscle contraction in several human diseases. An increased bronchial smooth muscle contractility, which might be a major cause of the airway hyperresponsiveness that is a characteristic feature of asthmatics, has also been reported in bronchial asthma. Here, we will discuss the role of RhoA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction in the pathogenesis of airway hyperresponsiveness. Agonist-induced Ca2+ sensitization is also inherent in bronchial smooth muscle. Since the Ca2+ sensitization is sensitive to a RhoA inactivator, C3 exoenzyme, and a Rho-kinase inhibitor, Y-27632, the RhoA/Rho-kinase pathway is involved in the signaling. It is of interest that the RhoA/Rho-kinase-mediated Ca2+ sensitization of bronchial smooth muscle contraction is markedly augmented in experimental asthma. Moreover, Y-27632 relaxes the bronchospasm induced by contractile agonists and antigens in vivo. Y-27632 also has an ability to inhibit airway hyperresponsiveness induced by antigen challenge. Thus, the RhoA/Rho-kinase pathway might be a potential target for the development of new treatments for asthma, especially in airway hyperresponsiveness.

New treatments for asthma.

1. Mary V. Lasley, MD* 1. *Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine, Northwest Asthma & Allergy Center, Seattle, WA After completing this article, readers should be able to: 1. Define asthma. 2. List conditions that mimic asthma. 3. Delineate the factors that predict the persistence of asthma. 4. Describe the objective measurements of pulmonary function required for evaluation and treatment of asthma. 5. Explain the role of anti-inflammatory medications in the management of persistent asthma. 6. Determine when a child should be referred to an asthma specialist. Over the past 15 years, the number of people affected by asthma has more than doubled. Asthma is the most common pediatric chronic disease, afflicting nearly 5 million children younger than age 18 years in the United States. Asthma affects 1 of every 13 schoolchildren. Every year, asthma accounts for more than 3 million physician visits and 200,000 pediatric hospitalizations, with rates highest among African-American children. Asthma mortality nearly doubled between 1980 and 1993 (17 and 32 asthma deaths per 1 million population, respectively). More than 5,500 people die from asthma every year. Asthma is a major cause of school absenteeism, with an estimated 10 million missed schooldays each year. The economic impact of asthma is enormous, approaching $3 billion annually. This encompasses direct costs such as medical expenses and indirect costs of parents and caregivers taking time away from work to care for their ill children, which has been estimated at $1 billion anually. Asthma severity is greater in urban minority populations, both African-American and Hispanic. Children living in inner cities often do not receive appropriate treatment to reduce their asthma severity and live in situations where it is difficult to control environmental exposures. Inflammation is present even in the airways of young patients who have mild asthma. A complex orchestration of inflammatory cells (eg, mast cells, eosinophils, T lymphocytes, and neutrophils), chemical mediators (eg, histamine, leukotrienes, platelet-activating factor, bradykinin), and chemotactic factors (eg, cytokines, eotaxin) results …