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Biomedical subjects

W W Busse

Publications and source records attributed to W W Busse.

At least 55 records · Page 3Linked to original sources
PubMed1999

Endothelial cells upregulate eosinophil superoxide generation via VCAM-1 expression.

BACKGROUND: In vitro eosinophil (EOS) adhesion to recombinant human (rh)-vascular cell adhesion molecule (VCAM)-1 stimulates superoxide anion (O2-) generation and enhances formyl-methionyl-leucyl phenylalanine (FMLP)-activated O2- generation. Therefore, EOS adhesion via VLA-4 to VCAM-1 expressed on endothelium may be instrumental in the selective recruitment and function of EOS in airway inflammation. OBJECTIVE: We hypothesized that EOS interaction with endothelial cells expressing VCAM-1 will undergo an enhancement in inflammatory function. METHODS: To determine this possibility, human umbilical vein endothelial cells (HUVEC) were stimulated with either a combination of interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha (100 pM) or medium alone for 24 h; the expression of adhesion proteins on HUVEC and their effect on EOS O2- generation was subsequently determined. RESULTS: As determined by both enzyme-linked immunosorbent assay and flow cytometry, IL-4 and TNFalpha acted synergistically to induce VCAM-1 expression on HUVEC. Treating HUVEC with IL-4/TNFalpha also increased EOS adhesion and primed subsequent FMLP (0.1 microM) activated EOS O2- generation. Although EOS adhesion was partially inhibited by both antialpha4 and antibeta2 monoclonal antibodies (MoAbs), O2- generation was completely inhibited by either antialpha4 integrin MoAb (HP1/2) or anti-VCAM MoAb (BBIG-V1). Furthermore, enhanced O2- generation, but not adhesion, associated with IL-4 + TNFalpha-treatment of HUVEC was inhibited when EOS were treated with the platelet activating factor (PAF)-antagonist WEB 2086 (20 microM), thus suggesting an involvement of PAF in priming EOS. However, paraformaldehyde fixation of IL-4/TFN-alpha treated HUVEC did not significantly alter EOS function. CONCLUSIONS: These results suggest EOS adhesion to endothelial cells via an VLA-4/VCAM-1 interaction may be important in the development of the function of this cell. Furthermore, our results suggest that modulation of EOS function involves two priming factors: EOS adhesion to HUVEC expressing VCAM-1 and PAF.

Adult↗
PubMed1999

Association of rhinovirus infections with asthma.

Rhinoviruses are the most common cause of the common cold, but they can cause more severe illnesses in people with underlying lung disorders such as asthma, chronic obstructive pulmonary disease, or cystic fibrosis. Epidemiologic studies with sensitive detection methods such as PCR have identified rhinovirus infection as a major source of asthma exacerbations in both children and adults, especially during the spring and fall. Since rhinoviruses cause little tissue destruction, it is presumed that the immune response to the infection may play an important role in the pathogenesis of rhinovirus-induced exacerbations of asthma. This review examines the epidemiologic association between rhinovirus infections and exacerbations of asthma and outlines current information on immune responses to rhinovirus infection and potential connections between antiviral responses and preexisting allergic inflammation. Finally, current and future strategies for treating rhinovirus infections and virus-induced exacerbations of asthma are discussed.

Animals↗
PubMed1999

Segmental antigen challenge increases fibronectin in bronchoalveolar lavage fluid.

Fibronectin may contribute to asthma pathogenesis by recruitment and activation of inflammatory cells, and by promotion of subepithelial fibrosis. Fibronectin is produced by several types of airway cells, including epithelial cells, fibroblasts, and alveolar macrophages. To test the hypothesis that antigen-induced airway inflammation is associated with increased local generation of fibronectin, segmental bronchoprovocation (SBP) with antigen and saline was performed in 17 atopic patients. Bronchoalveolar lavage (BAL) was performed at 5 min and 48 h after segmental challenge with saline or antigen. Fibronectin concentrations in BAL fluid, measured by enzyme-linked immunosorbent assay (ELISA), increased more than 5-fold 48 h after antigen challenge (65 [47 to 110] versus 407 [240 to 697] ng/ml, median and 25 to 75% interquartiles, p < 0.05). Fibronectin concentrations 48 h after antigen challenge correlated with histamine concentrations 5 min after antigen challenge and numbers of eosinophils, neutrophils, macrophages, and total cells in BAL fluid 48 h after antigen challenge. BAL was more enriched in fibronectin 48 h after challenge than would be predicted solely from increased permeability of plasma proteins. Western blot analysis showed that fibronectin in BAL fluid was largely intact and contained the extra domain-A (ED-A) splice variant of cellular fibronectin, indicative of local production. We conclude that antigen challenge in atopic subjects causes increased production of fibronectin by airway cells and speculate that this response may contribute to airway remodeling in allergic inflammation.

Adult↗
PubMed1999

Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness.

STUDY OBJECTIVES: To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge. DESIGN: Randomized, double-blind, placebo-controlled, multicenter study. SETTING: Thirty-one clinical centers in the United States. PATIENTS: Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70% of predicted values. Patients were not using inhaled corticosteroids. INTERVENTIONS: Twice-daily salmeterol aerosol, 42 microg, or placebo via metered-dose inhaler for 24 weeks. Backup albuterol was available. MEASUREMENTS AND RESULTS: Pulmonary function tests were performed before, during, and after treatment. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow (PEF) levels, and use of supplemental albuterol daily on diary cards. Methacholine challenges were performed 10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days posttreatment. Over 24 weeks of treatment, salmeterol provided significant (p < 0.001) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection. A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol treatment resulted in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo (p < 0.001). The use of salmeterol significantly reduced combined daytime asthma symptoms by 20% when compared to placebo (p = 0.005). A total of 34 and 48 exacerbations, respectively, were reported in the Salmeterol and placebo groups, and no evidence was present for a difference in the severity of asthma exacerbations between groups. Adverse event profiles were similar for the salmeterol and placebo groups. CONCLUSIONS: Regular long-term use of salmeterol aerosol resulted in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period. There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy. There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment. Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Administration, Inhalation↗
PubMed1999

The role of the common cold in asthma.

It has long been known that patients with viral respiratory infections develop temporary asthma-like symptoms or see a worsening of their existing asthmatic symptoms or develop full-blown asthma during the infection. It should not be surprising, in view of this observation, that these same viruses have been found to initiate the same inflammatory processes as seen and characterized in the asthmatic patient. This has clear implications for therapy of asthmatic patients.

Asthma↗
PubMed1998

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

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 the first 60 minutes after exercise. This measure summarized the extent and duration of bronchoconstriction after exercise. RESULTS: At 12 weeks, montelukast therapy offered significantly greater protection against exercise-induced bronchoconstriction than placebo therapy (expressed as the percentage of inhibition of the end points), as evidenced by the improvement in the area under the FEV1 curve (degree of inhibition, 47.4 percent; P=0.002). Montelukast therapy was also associated with a significant improvement in the maximal decrease in FEV1 after exercise (P=0.003) and the time from the maximal decrease in FEV1 to the return of lung function to within 5 percent of pre-exercise values (P=0.04). The differences between groups in the various measures of lung function were similar at 4, 8, and 12 weeks; there was no evidence of rebound worsening of lung function in the montelukast group after the washout period. After 12 weeks of treatment, patients in the montelukast group were more likely to rate their asthma control as better and less likely to require rescue therapy with a beta-agonist during or after exercise challenge. The rates of adverse events were similar in the two groups. CONCLUSIONS: As compared with placebo, once-daily treatment with montelukast provided significant protection against exercise-induced asthma over a 12-week period. Tolerance to the medication and rebound worsening of lung function after discontinuation of treatment were not seen.

Acetates↗
PubMed1998

Differential regulation of eosinophil adhesion and transmigration by pulmonary microvascular endothelial cells.

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-alpha + IL-4 (82.2 +/- 4.2% positive cells) > TNF-alpha (41.8 +/- 5.1%) > IL-1beta (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-1beta (21.2 +/- 1.4% migration) > TNF-alpha (12.6 +/- 2.6%) > TNF-alpha + IL-4 (9.1 +/- 2.0%). EOS adhesion was greatest with TNF-alpha + IL-4-treated HPMEC, was dependent on VCAM-1, and inhibited with anti-alpha4 integrin mAb (67.7 +/- 7.5% inhibition, p < 0.0005). In contrast, the highest EOS migration occurred across IL-1beta-treated HPMEC and was inhibited by anti-beta2 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., alpha4 and beta2 integrins on EOS.

Adult↗
PubMed1998

Eosinophils bind rhinovirus and activate virus-specific T cells.

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.

Adult↗
PubMed1998

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

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-á-vis other therapeutic agents--in preventing or blocking specific proinflammatory markers.

Administration, Inhalation↗
PubMed1998

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

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 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test. RESULTS: The mean baseline FEV1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo (p < 0.001). The mean changes in morning peak expiratory flow were 12, 22, 27, and 30 L/min in the 200, 400, 800, and 1600 microg budesonide total daily dose groups, respectively, and -27 L/min for the placebo group. A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1. 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.

Adolescent↗
PubMed1998

Theophylline inhibits the late asthmatic response to nighttime antigen challenge in patients with mild atopic asthma.

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 nebulization until the IAR (fall in FEV1 of > or =20%) occurred; spirometry was then measured hourly for 8 hours to establish the presence of LAR (fall in FEV1 > or =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. FEV1 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 FEV1 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 <.05) of inhaled antigen during theophylline phase, which would have been expected to result in a more pronounced LAR. Serum theophylline concentration at 8 AM on the day following antigen challenge was 9.6 +/- 1.1 mg/L (53 +/- 6 micromol/L). 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.

Adult↗
PubMed1998

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

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 E2 (PGE2) is produced through the actions of cyclooxygenase-2 (COX-2). Aspirin, but not acetaminophen, inhibits COX-2 activity. As PGE2 promotes TH2 and inhibits THI 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 PGE2 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.

Animals↗
PubMed1998

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

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.

Acute Disease↗
PubMed1998

Asthma.

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Animals↗