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Biomedical subjects

S E Wenzel

Publications and source records attributed to S E Wenzel.

At least 19 recordsLinked to original sources
PubMed2001

Improvement in health care utilization and pulmonary function with fluticasone propionate in patients with steroid-dependent asthma at a National Asthma Referral Center.

The impact of switching from other inhaled corticosteroids to fluticasone propionate was studied in patients with severe oral-steroid-dependent asthma over a 1-year period. In this open-label prospective study, patients on maintenance doses of oral and inhaled steroids were referred to a national asthma treatment center and were switchedfrom their previous inhaled corticosteroid to fluticasone propionate 880 microg BID. Compared with data collected from the year prior to enrollment, treatment with fluticasone propionate resulted in significant improvements in pulmonary function, oral steroid requirements, and health resource utilization. In addition, five patients were completely weaned off oral steroids.

Administration, Inhalation↗
PubMed2001

Persistent wheezing in very young children is associated with lower respiratory inflammation.

Despite advances in understanding the pathophysiology of asthma, morbidity and mortality in pediatrics continue to rise. Little is known about the initiation and chronicity of inflammation resulting in asthma in this young population. We evaluated 20 "wheezing" children (WC) (median age 14.9 mo) with a minimum of two episodes of wheezing or prolonged wheezing > or = 2 mo in a 6-mo period with bronchoscopy and bronchoalveolar lavage (BAL). Comparisons were made with six normal controls (NC) (median age 23.3 mo) undergoing general anesthesia for elective surgery. BAL fluid cell counts and differentials were determined. The eicosanoids, leukotriene (LT) B(4), LTE(4), prostaglandin (PG)E(2), and 15-hydroxyeicosatetraenoic acid (HETE) and the mast cell mediators, beta-tryptase and PGD(2), were evaluated by enzyme immunoassay (EIA). WC had significant elevations in total BAL cells/ml (p = 0.01), as well as, lymphocytes (LYMPH, p = 0.007), macrophages/monocytes (M&M, p = 0.02), polymorphonuclear cells (PMN, p = 0.02), epithelial cells (EPI, p = 0.03), and eosinophils (EOS, p = 0.04) compared with NC. Levels of PGE(2) (p = 0.0005), 15-HETE (p = 0.002), LTE(4) (p = 0.04), and LTB(4) (p = 0.05) were also increased in WC compared with NC, whereas PGD(2) and beta-tryptase were not. This study confirms that inflammation is present in the airways of very young WC and may differ from patterns seen in adults with asthma.

Age Factors↗
PubMed2001

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma.

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulairtrade mark, Merck) and zafirlukast (Accolatetrade mark, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflotrade mark, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.

Acetates↗
PubMed2000

Peripheral blood and airway tissue expression of transforming growth factor beta by neutrophils in asthmatic subjects and normal control subjects.

BACKGROUND: Airway remodeling may play an important role in asthma pathophysiology. Transforming growth factor beta (TGF-beta) has a critical role in the remodeling process. Although cellular sources for TGF-beta have been previously investigated in asthma airways, the expression, release, or both of TGF-beta from asthmatic airways and blood neutrophils has not been reported. OBJECTIVE: The current study evaluated the TGF-beta protein and messenger (m)RNA expression by airway and peripheral blood neutrophils in asthmatic and normal subjects. METHODS: TGF-beta protein expression by airway and peripheral blood neutrophils was detected by using immunocytochemistry. TGF-beta protein levels in blood neutrophil supernatant were measured by using an enzyme immunoassay. TGF-beta mRNA expression was evaluated by using reverse transcription-PCR. RESULTS: Higher numbers of TGF-beta(+) cells and neutrophils were found in airway tissue of asthmatic (n = 15) compared with normal subjects (n = 10). Although neutrophils in both asthmatic and normal airway tissue expressed TGF-beta protein and the percentage of neutrophils expressing TGF-beta was similar between the two groups, the total number of TGF-beta(+) neutrophils was higher in the asthmatic subjects (P =.01). Peripheral blood neutrophils from asthmatic (n = 5) and normal subjects (n = 7) also expressed TGF-beta protein and mRNA. Blood neutrophils from asthmatic subjects spontaneously released significantly higher levels of TGF-beta than those from normal subjects (P =.007). CONCLUSION: These data suggest that airway and blood neutrophils from both asthmatic and normal subjects can express and release TGF-beta. Higher levels of TGF-beta expression-release from asthmatic neutrophils indicate that neutrophils may be involved in the airway remodeling process of asthmatic subjects.

Adult↗
PubMed2000

Pathophysiology of severe asthma.

Although asthma affects nearly 8% of the adult population, most of these patients have mild-to-moderate disease that can be controlled with appropriate treatment. It is estimated, however, that 5% to 10% of patients with asthma have severe disease that is unresponsive to typical therapeutics, including corticosteroids. Because patients with severe asthma are disproportionately affected by their disease, in terms of both impaired lifestyle and health care costs, the National Heart, Lung, and Blood Institute sponsored a workshop on the pathogenesis of severe asthma. The goals of this workshop were to begin to define the characteristics of severe asthma. In these discussions, it was clear that many characteristics need to be considered in defining this phenotype of asthma, including symptoms, intensity of therapy (including administration of systemic corticosteroids), and impairment of lung function. Also discussed were potential mechanisms of severe asthma including the role of allergic diseases, which may play less of a role in severe asthma than in mild-to-moderate disease, and infections. A major limitation to control of severe asthma is the recalcitrant response of these patients to usual therapy including systemic corticosteroids; the potential of other therapies was reviewed. From these discussions, recommendations were made for future research needs to gain insights into a difficult therapeutic and possibly novel mechanistic area of asthma.

Asthma↗
PubMed1999

Increased T-cell receptor vbeta8+ T cells in bronchoalveolar lavage fluid of subjects with poorly controlled asthma: a potential role for microbial superantigens.

BACKGROUND: T cells are thought to play an important role in the pathogenesis of chronic asthma. The immunologic triggers that contribute to poorly controlled asthma are unknown but may include infectious agents. Superantigens (SAgs), which stimulate T cells expressing selected T-cell receptor (TCR) beta-chain variable (Vbeta) regions, are known to be an important mechanism by which microbes can contribute to T-cell activation and disease pathogenesis. OBJECTIVE: We sought to determine the potential role of SAgs in T-cell activation of patients with poorly controlled asthma. METHODS: We studied the TCR-Vbeta repertoire of bronchoalveolar lavage (BAL) cells and PBMCs from 9 subjects with poorly controlled asthma (FEV1 <75%), 7 subjects with well-controlled asthma (FEV1 >80%), and 8 normal control subjects with the use of anti-TCR-Vbeta-specific mAbs and flow cytometry. RESULTS: Subjects with poorly controlled asthma had a significantly higher expression of Vbeta8(+) T cells in BAL fluid than subjects with well-controlled asthma and normal control subjects (P <.01) and autologous PBMCs (P <.05). Increased Vbeta8(+) BAL T cells were present in CD4(+) (P <.01) and CD8(+) (P <.05) subsets, suggesting activation by SAgs. CONCLUSION: These results indicate that SAgs are a potential trigger of T-cell activation in poorly controlled asthma.

Adult↗
PubMed1999

Use of leukotriene antagonists in childhood asthma.

Leukotrienes have been shown to cause bronchoconstriction, increased mucus production, and airway inflammation, three critical features in asthma. Antileukotriene drugs were developed to inhibit the effects of these lipid mediators. This class of drugs represents the first new approach to asthma therapy in 25 years. The leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast, and the 5-lipoxygenase inhibitor, zileuton, are unique in their ability to target specific components of asthmatic inflammation. Although the role of these drugs continues to evolve, the antileukotrienes have demonstrated efficacy against exercise and allergen-induced bronchoconstriction and additive benefit for use in patients with symptomatic, moderate asthma on maintenance-inhaled corticosteroids. Further, they may be considered for primary use in patients with mild, persistent asthma, especially those who are steroid-phobic or who have compliance issues.

Anti-Asthmatic Agents↗
PubMed1999

Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma.

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCRbeta, which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCRbeta could account for glucocorticoid insensitivity. Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCRbeta immunoreactivity using a GCRbeta-specific antibody by immunohistochemical staining. Cell localization of GCRbeta expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCRbeta-immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCRbeta expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCRbeta in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCRbeta-positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCRbeta in airway T cells.

Adult↗
PubMed1999

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.

Adult↗
PubMed1999

Inhaled nonsteroidal anti-inflammatory medications in the treatment of asthma.

Asthma is characterized by airway inflammation even in the mildest cases. Multiple studies have confirmed evidence of significant elevations of inflammatory cells and mediators even at baseline in the airway of asthmatics. Cromolyn sodium (SCG) and nedocromil sodium (NS), the "nonsteroidal anti-inflammatory agents" are considered options for the management of mild persistent asthma in both adults and children as outlined by the Global Initiative for Asthma and the Expert Panel II, National Asthma Education and Prevention Program 1997 guidelines. These drugs may inhibit both the early and late asthmatic response, ostensibly by stabilizing mast cells and by reducing the total number of eosinophils and their recruitment. SCG and NS have extremely safe profiles, making them attractive for use even in young children. In addition to daily use for mild persistent asthma, SCG and NS are effective inhibitors of exercise-induced bronchospasm (EIB). Although these drugs are unlikely to eliminate the use of inhaled corticosteroids in patients with more significant obstructive airway disease, they have potentially beneficial steroid-sparing effects. Thus, the cromione, SCG and NS, are effective prophylactic drugs recommended for use in both adults and children in the management of mild persistent asthma, EIB, and potentially as modest steroid-sparing agents.

Administration, Inhalation↗
PubMed1998

New approaches to anti-inflammatory therapy for asthma.

Currently, corticosteroids are the therapy of choice for the inflammatory component of asthma. This class of drug provides powerful anti-inflammatory effects in most patients; however, these effects are not specific and in some cases may result in serious side effects. Also, many patients have difficulty adhering to therapy with inhaled forms of these drugs, which are administered by metered-dose inhalers up to several times per day. There are several other therapies that provide potential anti-inflammatory effects, but they are of low efficacy, with little definitive anti-inflammatory effect. While efforts are currently under way to improve corticosteroid therapy, other directions include the development of targeted anti-inflammatory agents. For example, the leukotrienes, a family of inflammatory mediators that have been shown to enhance bronchoconstriction and airway mucus secretion, have been the focus of numerous investigations. Specific leukotriene receptor antagonists and synthesis inhibitors have been developed and are currently showing promise in clinical trials; one leukotriene receptor antagonist (zafirlukast) and one 5-lipoxygenase inhibitor (zileuton) were recently approved by the United States Food and Drug Administration for the treatment of asthma.

Anti-Asthmatic Agents↗
PubMed1998

Immunoaffinity resin for purification of urinary leukotriene E4.

Urinary leukotriene E4 (LTE4) has been used as an index of total leukotriene synthesis. A wide variety of methods have been applied to measure LTE4 which has made direct comparison of urinary levels reported by different laboratories difficult. A new peptidoleukotriene immunoaffinity resin was utilized for urinary LTE4 purification in a method that is easy and inexpensive, utilizing commercially available reagents. This method is described and compared to other methods. LTE4 (50-250 pg/mL) added to a urine extract was quantitatively recovered using the immunoaffinity resin. Similarly, LTE4 (50-400 pg/mL) added to urine was recovered between 63 and 76%. The coefficient of variation of samples purified and quantified on the same or on different days ranged from 8-10%. There was a strong correlation (r2 = 0.95) between LTE4 concentrations determined after immunofiltration and immunoaffinity purification. Although there was a good correlation between urinary LTE4 levels measured without purification compared to after immunoaffinity purification, the high y-intercept of 179 indicates the presence of interfering substances in unpurified urine. Urinary LTE4 in normal healthy adults was 80 +/- 7 pg/mg creatinine, similar to that previously reported following HPLC or immunofiltration purification. Urinary LTE4 was also measured in healthy children (age 3-12) and found to be 103 +/- 9.

Adult↗
PubMed1998

Efficacy, safety, and effects on quality of life of salmeterol versus albuterol in patients with mild to moderate persistent asthma.

BACKGROUND: Salmeterol xinafoate is a long-acting, highly selective, beta2-adrenergic agonist that produces bronchodilation and clinically significant improvement in pulmonary function for up to 12 hours in patients with asthma. OBJECTIVE: To evaluate the impact on asthma-specific quality of life, efficacy, and safety of salmeterol versus albuterol in adult patients with mild-to-moderate persistent asthma. METHODS: A randomized, double-blind, double-dummy, parallel-group, multicenter study was conducted in 539 adult asthma patients over 12 weeks. Patients were randomized to receive either salmeterol 42 microg via metered-dose inhaler twice daily or albuterol 180 microg four times daily. Upon entry into the study, 46% of patients were being treated with an inhaled corticosteroid and were allowed to continue treatment throughout the study. Pulmonary function and asthma symptoms were monitored daily, and patients completed the Asthma Quality of Life Questionnaire (AQLQ) at baseline and after 4, 8, and 12 weeks of treatment. RESULTS: Treatment with salmeterol twice daily produced significantly greater improvements from baseline in all quality of life domain ("Activity Limitation," "Asthma Symptoms," "Emotional Function," "Environmental Exposure") scores and in the global AQLQ score at 12 weeks (P < or = .038) compared with albuterol treatment four times daily. Pulmonary function and asthma symptoms were also significantly improved with salmeterol compared with albuterol. CONCLUSIONS: Salmeterol 42 microg administered twice daily is significantly more effective than albuterol 180 microg four times daily for improving asthma-specific quality of life, controlling asthma symptoms, and improving pulmonary function in patients with mild-to-moderate persistent asthma. Furthermore, those improvements were maintained over a 12-week period.

Adolescent↗
PubMed1998

Factors determining the severity of asthma.

Asthma typically can range from a disease of very mild and intermittent symptoms to one of debilitating and life-threatening disease. However, the factors that control these differences remain poorly understood. It is likely that the factors controlling the severity of asthma are many and dependent on each other. Potential factors include: (i) inflammatory; (ii) structural; (iii) hereditary/congenital; (iv) environmental; and (v) psychological/emotional; each potentially interacting and influencing the other. Finally, the question remains as to whether all asthmatics, no matter what their initial severity, potentially can develop severe disease, or whether only a certain subgroup will become severe.

Asthma↗
PubMed1998

Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease.

Chronic airway inflammation and remodeling, including fibrosis, have been proposed as important contributors to asthma pathophysiology. Previous studies of airway fibrosis have been performed mainly in mild and moderate asthmatics at the subepithelial "basement membrane" (SBM) level. The current study was designed to evaluate the large airway SBM thickness and submucosal collagen deposition, as measured by three different collagen staining methods, in endobronchial biopsies from 17 severe, nine moderate, and seven mild asthmatics, as well as eight normal control subjects. Tissue eosinophils and transforming growth factor-beta (TGF-beta) immunoreactivity were also examined. There were no statistically significant differences in the SBM thickness, submucosal collagen deposition, eosinophil numbers, or TGF-beta positive cells among the three groups of asthmatics and the normal control subjects. It was only when examining all asthmatics (n = 33) together, that a modestly thickened SBM (p = 0.04), as evaluated by collagen type III immunostaining, was observed as compared with normal control subjects. Despite this difference, no significant differences were found in the amount of submucosal collagen deposition and the number of eosinophils or TGF-beta expressing cells when comparing total asthmatics and normal control subjects. Additionally, no significant correlations were found between collagen deposition and eosinophil count, TGF-beta expression level, FEV1, or duration of asthma. These results suggest that although increased collagen deposition in the SBM at the large airway level is a characteristic of asthma, it may not explain the differences in severity of asthma.

Adult↗