Showing papers by "William W. Busse published in 1998"

Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction.

Abstract: Background Patients with mild asthma frequently have only exercise-induced bronchoconstriction, a symptom of inadequate control of asthma. We evaluated the ability of montelukast, a leukotriene-receptor antagonist, to protect such patients against exercise-induced bronchoconstriction. Methods We randomly assigned 110 patients (age, 15 to 45 years) with mild asthma and a decrease in the forced expiratory volume in one second (FEV1) of at least 20 percent after exercise on two occasions during a placebo run-in period to receive 10 mg of montelukast (54 patients) or placebo (56 patients) once daily at bedtime for 12 weeks in a double-blind study. Treatment was followed by a two-week, single-blind washout period during which all patients received placebo. Exercise challenges were performed at base line; 20 to 24 hours after dosing at weeks 4, 8, and 12; and at the end of the washout period. The primary end point was the area under the curve for FEV1 (expressed as the percent change from base-line values) in t...

Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma

Abstract: Background: Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent. Objectives: The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma. Methods: In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 μg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV 1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test. Results: The mean baseline FEV 1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo ( p 1 . Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo. There were no clinically significant differences in treatment-related adverse experiences among groups. Conclusions: Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses. It was well tolerated and significantly more effective than placebo.

Inflammation in asthma: the cornerstone of the disease and target of therapy.

Abstract: Asthma is a chronic disease associated with variable levels of airflow obstruction. Considerable evidence has been obtained to show that airway inflammation is a major factor in the pathogenesis of asthma in associated bronchial hyperresponsiveness, and in the level of disease severity. The inflammatory pattern in asthma is multicellular in nature, with mast cells, neutrophils, eosinophils, T lymphocytes, and epithelial cells participating in the response. Furthermore, it is known that mediators, cytokines, and chemokines from these cells contribute to the orchestration of the inflammatory process. Because airway inflammation appears to be a critical etiologic feature of asthma, it has become the target of therapy. In this review the features of airway inflammation will be examined, and the effect of therapeutic agents on markers of airway injury will be discussed. Establishing, understanding, and finally controlling the features of airway inflammation have given insight to disease pathogenesis and the effectiveness of various treatments. The integral role of inhaled corticosteroids in modifying the complex inflammatory component of asthma will be explored, with special focus on the high degree of efficacy associated with this treatment--vis-a-vis other therapeutic agents--in preventing or blocking specific proinflammatory markers.

The Role of Leukotriene Modifiers in the Treatment of Asthma

Abstract: Asthma is a complex syndrome characterized by variable obstruction to airflow, bronchial hyperresponsiveness, and inflammation. The initiation and propagation of airway inflammation arises from many factors, including mediators generated by resident airway cells and recruited leukocytes (1). Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid, an integral component of the cell membrane (2). A role for leukotrienes in the pathogenesis of asthma has been suggested by their biologic activities, which produce effects that mimic those of clinical asthma, and by the effects of either inhibition of leukotriene production (5-lipoxygenase inhibitors) or antagonism of leukotriene binding to cellular receptors (leukotriene D 4 -receptor antagonists). The recent U.S. Food and Drug Administration (FDA) approval of a leukotriene-receptor antagonist, zafirlukast (Accolate), and a leukotriene synthesis inhibitor, zileuton (Zyflo), provides the first mediator-specific therapy for asthma. This review will consider the biochemistry of the leukotrienes, their biologic role in asthma, and the therapeutic potential of drugs that alter the production or action of leukotrienes, as well as provide guidelines for the use of leukotriene modifiers in patients with asthma.

Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma

Abstract: Background The prevalence of asthma, atopic eczema, and allergic rhinitis has increased over the last three decades in Western countries. Speculation on the causes of this trend have focused on changes in environmental factors. We hypothesize that the decreased use of aspirin in favor of acetaminophen, due to the association of aspirin with Reye's syndrome during febrile respiratory infections, may be contributing to these trends in the United States. Data sources A detailed literature search was conducted utilizing MEDLINE. Studies considered relevant and important involving both humans and animals in English language were used. Hypothesis In the United States, the documented prevalence of childhood asthma has increased since 1970, but the rate of this increase accelerated upward beginning in the early 1980s when the use of pediatric aspirin decreased. During the resolution of common respiratory viral infections, prostaglandin E 2 (PGE 2 ) is produced through the actions of cyclooxygenase-2 (COX-2). Aspirin, but not acetaminophen, inhibits COX-2 activity. As PGE 2 promotes TH2 and inhibits TH1 type cytokine generation, we hypothesize that the decreased use of aspirin may be a factor in facilitating allergic sensitization and asthma by augmenting the relative TH1/TH2 cytokine imbalance in genetically predisposed children. Conclusion We have presented an hypothesis based upon epidemiologic trends, known biologic effects of cytokines and PGE 2 on allergic sensitization, and a potentially relevant pharmacologic effect of aspirin to explain a component of the increasing prevalence of childhood asthma in the United States. We suggest this theory be examined further in animal models as well as in other countries where the prevalence of childhood asthma is increasing.

Eosinophils Bind Rhinovirus and Activate Virus-Specific T Cells

Abstract: Episodes of virus-induced exacerbations of asthma are accompanied by increased eosinophils (EOS) in respiratory secretions and evidence of EOS degranulation. Although rhinoviruses (RV) are the viruses most often implicated in exacerbations of asthma in both children and adults, little is known about the immune response to this group of viruses and, in particular, EOS-RV interactions. To define such interactions, we incubated human rhinovirus type 16 (RV16), a serotype using ICAM-1 as a receptor, with EOS purified from PBMC, and measured EOS-RV binding, EOS-mediated Ag presentation and T cell activation, and EOS cell surface marker expression and superoxide production. Significant RV16 binding occurred to EOS that were pretreated with granulocyte-macrophage CSF, and this binding was inhibited by anti-ICAM-1 mAb. EOS also presented viral Ags to RV16-specific T cells, causing T cell proliferation and secretion of IFN-gamma. RV16 induced a significant shift from CD18dim to CD18bright, but did not affect EOS expression of CD54, CD69, or HLA-DR. Finally, RV16 did not induce superoxide production from peripheral blood EOS. These findings suggest that RV16 also binds to airway EOS, which resemble granulocyte-macrophage CSF-treated blood EOS in terms of high expression of ICAM-1. Furthermore, our findings suggest that EOS could participate in RV-induced immune responses through Ag presentation and T cell activation. By activating RV-specific T cells, EOS may play an important role in the initiation of antiviral T cell responses, and these effects could also contribute to enhanced airway inflammation and increased asthma symptoms in susceptible individuals.

Differential Regulation of Eosinophil Adhesion and Transmigration by Pulmonary Microvascular Endothelial Cells

Abstract: In bronchial asthma, eosinophils (EOS) adhere to, and migrate across, the lung microvasculature to exert their effector functions in the airways. This study was conducted to determine the effect of cytokines on adhesion molecule expression on human pulmonary microvascular endothelial cells (HPMEC) and the influence of these molecules on EOS adhesion and transmigration in vitro. Unlike ICAM-1 expression (>80% positive cytokine-treated HPMEC by flow cytometry), VCAM-1 expression varied with the cytokine(s) pretreatment; the order of potency was: TNF-α + IL-4 (82.2 ± 4.2% positive cells) > TNF-α (41.8 ± 5.1%) > IL-1β (20.8 ± 4.7%). IL-4 alone had no effect on either ICAM-1 or VCAM-1 expression. EOS adhesion to cytokine-treated HPMEC followed the same order as that observed for VCAM-1 expression. Interestingly, EOS migration across cytokine-treated HPMEC varied inversely with VCAM-1 expression on, and EOS adhesion to, HPMEC; IL-1β (21.2 ± 1.4% migration) > TNF-α (12.6 ± 2.6%) > TNF-α + IL-4 (9.1 ± 2.0%). EOS adhesion was greatest with TNF-α + IL-4-treated HPMEC, was dependent on VCAM-1, and inhibited with anti-α4 integrin mAb (67.7 ± 7.5% inhibition, p < 0.0005). In contrast, the highest EOS migration occurred across IL-1β-treated HPMEC and was inhibited by anti-β2 integrin mAb (40.4 ± 2.5% inhibition, p < 0.005). Viable HPMEC were required for EOS migration but not adhesion. Our results suggest that EOS adhesion and transmigration are differentially regulated by VCAM-1 and ICAM-1 expression and the interaction of these adhesion proteins with their respective counterligands, i.e., α4 and β2 integrins on EOS.

Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function.

Abstract: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin superfamily adhesion molecules on vascular endothelium and important in the development of eosinophil (EOS) accumulation in allergic inflammation. To define the role of these adhesion proteins in EOS inflammation, peripheral blood EOS from allergic donors were incubated in either buffer (control)-, recombinant human (rh)-VCAM-1-, or rh-ICAM-1-coated plates, and the effects of these adhesion proteins on EOS effector functions were determined. VCAM-1 induced spontaneous EOS adhesion whereas EOS adhesion to ICAM-1 required a second signal, such as granulocyte macrophage colony-stimulating factor (GM-CSF). Although only VCAM-1 stimulated EOS superoxide anion (O2-) generation, the addition of GM-CSF (100 pM) to the reactions resulted in a greater and equivalent production of O2- with VCAM-1 and ICAM-1. In the presence of GM-CSF, ICAM-1 and VCAM-1 caused significant release of EOS-derived neurotoxin (EDN). Moreover, only ICAM-1 (no GM-CSF) promoted calcium ionophore A23187 (0.2 microM)-induced EOS leukotriene C4 (LTC4). Enhanced O2- generation, EDN release, and LTC4 generation observed with ICAM-1 and VCAM-1 were significantly inhibited by anti-beta2-integrin antibody. These results suggest that ICAM-1 and VCAM-1 are important in determining the eventual function of airway EOS.

Asthma in non-inner city Head Start children.

Abstract: Objective. Asthma is a significant cause of morbidity and mortality in children. The objective of this study was to determine whether the federal program Head Start in Dane County, Wisconsin, could be used as a mechanism to identify preschool-aged children with asthma. Design. Five-year, cross-sectional survey of parents with children enrolled in Head Start. Methods. Investigator-administered asthma screening questionnaire to parents of enrolling Head Start children in Dane County, Wisconsin. Measurements. Asthma prevalence and asthma-related health care use, including emergency department visits, hospitalizations, and medication usage, were measured using an asthma screening questionnaire developed by investigators. Results. Information was gathered on 2215 children. The prevalence of physician-diagnosed asthma in the screened children was 15.8%. Parental reports of physician-diagnosed asthma were validated in a subset of 133 children, with a 98.5% confirmation rate. Independent risk factors for asthma included male gender (relative risk, 1.4) and African-American ethnicity (relative risk, 1.4). Asthma-related morbidity was substantial with 26.7% of identified children hospitalized for asthma and 54.5% with an emergency department visit during their lifetime. The majority of children (46.4%) were treated with intermittent, quick relief medications (β-agonists) alone, whereas only 6.1% were on daily, long-term controller medications. Conclusions. Asthma screening through a Head Start program provides an effective means of targeting preschool-aged children from socioeconomic groups at high risk for asthma. Identification of children early in the disease course and those at high risk for asthma provides an ideal opportunity for the implementation of preventive and therapeutic interventions.

Interleukin 5 signals through Shc and Grb2 in human eosinophils.

Abstract: Eosinophils are potent effector cells contributing to allergic inflammation and asthma. The differentiation, recruitment, and effector functions of eosinophils are greatly affected by interleukin (IL)-5. In the eosinophil, signal transduction pathways including Jak–STAT and Ras–Raf–MAP kinase are stimulated by IL-5 and enzymatic activation of tyrosine kinases Jak-2 and Lyn has been demonstrated. The participation of adapter proteins in the responses of the Ras–Raf–MAP kinase pathway has been documented in many cytokine family receptors but the expression and activation of these proteins have not been demonstrated in eosinophils. In these studies, we have found three isoforms of the adapter protein, Shc, to be expressed in eosinophils. One of these isoforms, p52 Shc, was tyrosine phosphorylated following IL-5 treatment of eosinophils. A second adapter protein, Grb2, coimmunoprecipitated with Shc following IL-5 stimulation of eosinophils. Furthermore, p52 Shc was increasingly associated with a cell fraction...

The Role and Contribution of Leukotrienes in Asthma

Abstract: Learning objectives Reading this article will reinforce the reader's knowledge of the biochemistry and pharmacology of leukotrienes (LTs), including the enzymes and cells involved in their synthesis, the receptors that mediate their biologic effects, and the evidence that cysteinyl leukotrienes (CysLT) may play an important role in asthma. The 5-lipoxygenase inhibitors, 5-lipoxygenase-activating protein antagonists, and Cys LT receptor antagonists are three classes of LTs modulators now in clinical use. The effects of these agents in clinical models of asthma induced by allergens, exercise, and aspirin and in multicenter asthma trials are reviewed. Data sources Key papers published in peer-reviewed journals. Study selection Key papers published in peer-reviewed journals. Conclusions The pharmacology of these new medications and experience in clinical trials suggest that they may play a therapeutic role in the treatment of asthma.

Increased tumor necrosis factor-alpha (TNF-alpha) gene expression in parainfluenza type 1 (Sendai) virus-induced bronchiolar fibrosis.

Abstract: Increased airway resistance and airway hyperresponsiveness induced in rats by infection with parainfluenza type I (Sendai) virus is associated with bronchiolar fibrosis. To determine whether increased tumor necrosis factor (TNF)-alpha gene expression is an important regulatory event in virus-induced bronchiolar fibrosis, pulmonary TNF-alpha mRNA and protein expression was assessed in rat strains that are susceptible (Brown Norway; BN) and resistant (Fischer 344; F344) to virus-induced bronchiolar fibrosis. Virus-inoculated BN rats had increased TNF-alpha pulmonary mRNA levels (P < 0.05) and increased numbers of bronchiolar macrophages and fibroblasts expressing TNF-alpha protein compared with virus-inoculated F344 rats (P < 0.05). Virus inoculation also induced elevated TNF-alpha mRNA and protein levels (P < 0.05) in cultured rat alveolar macrophages (NR8383 cells). A 55-kd soluble TNF receptor-immunoglobulin G fusion protein (sTNFR-IgG) was used to inhibit TNF-alpha bioactivity in virus-inoculated BN rats. Treated rats had fewer proliferating bronchiolar fibroblasts, as detected by bromodeoxyuridine incorporation, compared with virus-inoculated control rats (P < 0.05). There was also increased mortality in p55sTNFR-IgG-treated virus-inoculated rats associated with increased viral replication and decreased numbers of macrophages and lymphocytes in bronchoalveolar lavage fluid (P < 0.05). The results of this study indicate that 1) Sendai virus can directly up-regulate TNF-alpha mRNA and protein expression in macrophages, 2) TNF-alpha is an important mediator of virus-induced bronchiolar fibrosis, and 3) TNF-alpha has a critical role in the termination of Sendai viral replication in the lung.

Mechanisms of acute eosinophilic inflammation in a case of acute eosinophilic pneumonia in a 14-year-old girl

Abstract: BACKGROUND: Acute eosinophilic pneumonia (AEP) is characterized by respiratory distress, eosinophilic infiltration in the lung, acute onset, resolution of symptoms with corticosteroids and the absence of relapse. Studies to identify the pathophysiology of AEP in adults have demonstrated eosinophil activation in the BAL fluid, and the presence of high levels of interleukin 5 (IL-5) in the BAL. OBJECTIVE: To investigate the pathophysiology of AEP with pleural effusion in a paediatric patient. METHODS: ECP levels in the BALand pleural fluid was determined by radioimmunoassay. IL-5 and GM-CSF concentrations in the BAL and pleural fluid were measured by Elisa. Immunohistochemistry studies performed on open lung biopsy included a specific ICAM-1 immunostaining and a ECP specific immunostaining (EG2+). RESULTS: High levels of ECP were found in the BAL (5 microg/L) and pleural fluid (750 microg/L) demonstrating eosinophil activation at these sites. Immunohistochemistry illustrated activated (EG2+) eosinophils in the interalveolar septa and alveolar space and detected increased expression of ICAM-1 on alveolar epithelial cells. High levels of IL-5 were measured in the BAL (1334 pg/mL) and pleural fluid (7014 pg/mL), while elevated concentrations of GM-CSF (150 pg/mL) were found in the BAL. CONCLUSION: We conclude that in this paediatric patient with AEP activated eosinophils were present in the BAL fluid, in the interalveolar septa and in the pleural space while increased ICAM-1 expression was detected on alveolar epithelial cells, contributing, at least partly, for their adhesive interactions. IL-5 and GM-CSF are likely important to the massive eosinophil recruitment and activation in the lung, while IL-5 is probably related to eosinophil accumulation and activation in the pleural space. Thus, lung generation of eosinophil-active cytokines is central to the pathophysiology of AEP in paediatric patients.

Theophylline Inhibits the Late Asthmatic Response to Nighttime Antigen Challenge in Patients with Mild Atopic Asthma

Abstract: Background Inhaled antigen at night causes a more pronounced late asthmatic response (LAR) when compared with daytime challenges. Chronopharmacology with controlled-release theophylline given in the evening leads to a peak serum theophylline concentration (STC) in early morning which coincides with LAR that follows an evening challenge. Objective To evaluate the effect of controlled-release theophylline given with the evening meal on the immediate asthmatic response (IAR) and LAR following nighttime antigen challenge in patients with mild atopic asthma. Methods To qualify, subjects underwent antigen bronchoprovocation by graded nubulization until the IAR (fall in FEV 1 of >/= 20%) occurred; spirometry was then measured hourly for 8 hours to establish the presence of LAR (fall in FEV 1 >/=15%). After 2 weeks of randomized, double-blind crossover treatment with either theophylline [target STC of 10 to 15 mg/L, (56 to 83 micromol/L)] or placebo, inhaled antigen challenge was performed at 10 pm in each subject. FEV 1 values were measured immediately and then hourly for 8 hours following antigen challenge. Results Twelve subjects completed the study. During the placebo phase, the maximal fall in FEV 1 during LAR was 39 ± 3 % (mean ± SEM) compared with 31 ± 4% fall during theophylline treatment phase ( P = .01). A reduction in LAR occurred despite higher dose ( P Conclusion Nocturnal administration of controlled-release theophylline increases the tolerance to inhaled antigen and reduces severity of LAR. Because the LAR is linked to airway inflammation, these data support the possibility of antiinflammatory effects associated with theophylline use.

The Role of Rhinoviruses in Virus-Induced Asthma

Abstract: Publisher Summary Viral respiratory infections influence airway function and asthma through two distinct pathways. In infancy, respiratory viral infections, particularly respiratory syncytial virus (RSV), provoke wheezing. Infants with reduced lung function are at greatest risk for developing wheezing with RSV infection, yet only a subset of wheezing infants will go on to develop persistent asthma. Viral infections are the most important trigger for acute asthma symptoms in children, and this association exists in many adults with asthma. Experimental models that combine viral infection and allergen exposure have identified potential links between virus- and allergen-induced inflammation, and suggest several possible mechanisms by which virus-induced cytokines could enhance pre-existing airway inflammation in asthma. While there is an increasing amount of information suggesting that cytokines may be an important part of this association, their role must be verified with additional studies comparing the upper and lower airway immune responses to viral infections in people with asthma versus normal controls.

Current research and future needs in allergic rhinitis and asthma

Abstract: Although effective therapies are available to treat asthma and allergic rhinitis, research is now focused on defining the cause of these disorders, including an in-depth analysis of the role of the inflammatory process. An enhanced understanding of the mechanism of the asthmatic inflammatory response should aid in the discovery of more-targeted therapies and preventative

Discussion Session A: The early life origins of asthma

Abstract: Reply: D. A. Meyers Locus heterogeneity is a significant problem in many genetic studies of common complex disorders. It would be useful if we had an asthma subtype that is highly heritable, such as early age-of-onset in cancer studies. However, to date, we do not have such a phenotype and need to deal with locus heterogeneity in a statistical manner. Conditional analyses allow us to divide families based on linkage evidence. This may not represent a significant problem in mapping regions, but will present major difficulties in fine mapping and gene identification.