Virus-induced airway hyperresponsiveness and asthma.
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Asthma↗
Biomedical subjects
W W Busse
Publications and source records attributed to W W Busse.
Interleukin 5 signals through Shc and Grb2 in human eosinophils.
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 resistant to detergent solubilization, following IL-5 administration. This cell fraction of limited detergent solubility is a complex mixture of proteins and the adapter protein Grb2, the tyrosine kinases Jak-2 and Lyn, the nucleotide exchange factor Vav, and the serine-threonine kinases p45 MAP kinase, Raf-1, and PKCbeta, were distributed either wholly or partially in the same fraction, as were the cytoskeletal proteins actin and vimentin. Only p52 Shc, however, demonstrated discernibly increased association with this fraction following IL-5 stimulation of eosinophils. These data suggest that IL-5 activates a signal transduction pathway utilizing the adapter proteins Shc and Grb2 in the human eosinophil.
Adaptor Proteins, Signal Transducing↗
Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function.
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.
Adult↗
Asthma in non-inner city Head Start children.
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 (beta-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.
Asthma↗
Efficacy, safety, and impact on quality of life of salmeterol in patients with moderate persistent asthma.
OBJECTIVE: To evaluate the efficacy, safety, and impact on asthma-specific quality of life of salmeterol, a highly selective, long-acting beta 2-agonist, compared with that of placebo (i.e., "as-needed" albuterol). STUDY DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multicenter study. PATIENTS AND METHODS: Five hundred thirty-eight nonsmoking symptomatic patients 12 years of age and older meeting American Thoracic Society asthma criteria were enrolled at 55 outpatient clinics; 443 patients completed the study. Patients were randomly assigned to treatment with either salmeterol aerosol 42 micrograms twice daily or placebo (as-needed albuterol) for 12 weeks. We assessed changes in quality of life using the Asthma Quality of Life Questionnaire (AQLQ). Efficacy measurements included daily peak expiratory flow (PEF) rate, daytime and nighttime asthma symptoms, results of pulmonary function tests, and supplemental albuterol use. Patients recorded their PEF rate, supplemental albuterol use, and asthma-related symptoms daily. Pulmonary function tests and AQLQ assessments were performed at baseline and after 4, 8, and 12 weeks of treatment. Safety measurements included vital signs, physical examination, and reports of clinical adverse events at baseline and after 4, 8, and 12 weeks of treatment. RESULTS: Mean changes from baseline in AQLQ global and domain scores were significantly greater in the salmeterol group compared with the placebo group (P < 0.001). Patients treated with salmeterol also had significant improvements in mean PEF rates, supplemental albuterol use, asthma symptom scores, and forced expiratory volume in 1 second compared with those given placebo. Both salmeterol and placebo were well tolerated and were not associated with any clinically significant changes in vital signs or physical examination findings. CONCLUSIONS: Salmeterol 42 micrograms twice daily resulted in significantly greater improvements in asthma-specific quality of life, pulmonary function, and asthma symptoms compared with placebo (as-needed albuterol) in patients with moderate persistent asthma.
Adolescent↗
Increased tumor necrosis factor-alpha (TNF-alpha) gene expression in parainfluenza type 1 (Sendai) virus-induced bronchiolar fibrosis.
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.
Animals↗
Clinical assessment of patients.
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Asthma↗
Leukotrienes and inflammation.
Leukotrienes are potent pro-inflammatory mediators that appear to contribute to pathophysiologic features of asthma. For example, cysteinyl leukotrienes contract airway smooth muscle, increase microvascular permeability, stimulate mucus secretion, decrease mucociliary clearance, and appear capable of recruiting eosinophils into the airways. Segmental antigen bronchoprovocation in patients with asthma increases LTC4 concentrations in bronchoalveolar lavage fluid, which correlates with an influx of eosinophils into the airways. LTB4, in comparison, selectively affects neutrophil functions. Intratracheal instillation of LTB4 produced a selective recruitment of neutrophils into the lung. These effects suggest that leukotrienes contribute significantly to the inflammatory components of asthma.
Animals↗
Asthma.
For unknown reasons, the morbidity and mortality from asthma are increasing in many parts of the world, making it a global health concern. The heterogeneous nature of the clinical manifestations and therapeutic responses of asthma in both adult and pediatric patients indicate that it may be more of a syndrome rather than a specific disease entity. Numerous factors, including viral infections, allergen and irritant exposure, and exercise, among others, complicate both the short- and long-term management of asthma. Therapeutic intervention has focused on the appreciation that airway obstruction in asthma consists of bronchial smooth muscle spasm and variable degrees of airway inflammation characterized by edema, mucous secretion, and the influx of a variety of inflammatory cells. Choosing appropriate medications depends on the disease severity (intermittent, mild persistent, moderate persistent, severe persistent), patterns of disease activity (exacerbations related to viruses, allergens, exercise, etc), and the age at onset (infancy, childhood, adulthood).
Asthma↗
The role of respiratory viruses in asthma.
Respiratory infections are common causes of increased asthma for patients of all ages. Current evidence indicates that viral, and not bacterial, infections are the most important respiratory illnesses which increase the severity of asthma. Of the respiratory viral infections associated with increased asthma, rhinoviruses, i.e. the cause of common colds, have proven to be the virus most often found in association with increased asthma severity. Although the association between rhinovirus infections and asthma is most dramatically illustrated in children, asthma patients of all ages can be affected and the attacks of asthma can be severe. Studies to establish the mechanisms by which rhinoviruses enhance asthma severity have begun to focus on how this virus promotes allergic inflammation. We have found that experimental rhinovirus infections enhance airway responsiveness and, perhaps most importantly, the likelihood that a late allergic reaction will occur to an antigen challenge. Furthermore, using bronchoscopy and segmental antigen challenge, we have found that rhinovirus infections promote mast cell release of histamine and the recruitment of eosinophils to the airways. These data support the concept that rhinovirus infections act to promote allergic inflammation and by this mechanism increase both the likelihood of asthma occurring and the severity of wheezing.
Asthma↗
Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis.
BACKGROUND: Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. OBJECTIVE: We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. METHODS: Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. RESULTS: Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE-dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (< or = 24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. CONCLUSIONS: Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases.
Adolescent↗
Late allergic airway response to segmental bronchopulmonary provocation in allergic subjects is related to peripheral blood basophil histamine release.
BACKGROUND: Basophil histamine release has been found to correlate with the presence and severity of allergic disease. However, it remains to be established whether airway response to antigen is related to basophil involvement and its release of histamine. OBJECTIVE: The purpose of this study was to investigate whether the intensity of airway response to an inhaled antigen challenge in allergic subjects is related to IgE-dependent peripheral blood basophil histamine release. METHODS: The response to segmental bronchoprovocation with antigen was examined in 34 subjects with allergic rhinitis. Bronchoalveolar lavage samples were obtained 5 minutes (immediate response) and 48 hours (late response) after allergen challenge. Peripheral blood maximal basophil histamine release (MBHR) in response to in vitro antigen stimulation was determined in each subject before segmental bronchoprovocation. RESULTS: Bronchoalveolar lavage samples obtained during immediate response showed an increase in histamine, whereas the late response was noted for a marked enhancement in airway cells, particularly eosinophils. Interestingly, a significant correlation (r = 0.73, p < 0.0001, Spearman Rank test) was noted between MBHR and intensity of bronchoalveolar lavage eosinophilia at 48 hours. Furthermore, subjects with high (> or = 20%) MBHR had significantly higher total cells and eosinophils in bronchoalveolar lavage fluid 48 hours after antigen segmental bronchoprovocation when compared with subjects with low (< 20%) MBHR. CONCLUSION: Our data suggest that the intensity of airway eosinophilia in response to antigen challenge is correlated with the magnitude of basophil mediator release in allergic subjects.
Adult↗
Inhibitory effect of cetirizine on cytokine-enhanced in vitro eosinophil survival.
BACKGROUND: Cetirizine is an antihistamine that inhibits in vivo eosinophil influx into the inflamed airways following allergen challenge, and in vitro eosinophil chemotaxis and adhesion. Since eosinophils are proposed to have an important role in the pathophysiology of asthma and allergic disease, the effects of cetirizine on eosinophil function may be a mechanism of this agent's therapeutic regulation of the allergic reaction. OBJECTIVE: To determine the effect of cetirizine on in vitro eosinophil survival. METHODS: Using human eosinophils isolated from patients with allergic rhinitis, the cells were cultured in vitro for 48 to 72 hours with medium, cetirizine, or dexamethasone in the presence of IL-5, IL-3, or GM-CSF. Eosinophil survival was assessed by trypan blue exclusion. RESULTS: In the presence of IL-5, but not GM-CSF or IL-3 100 microM cetirizine significantly inhibited eosinophil survival at 48 and 72 hours; the magnitude of this inhibition was dependent on cytokine concentration. Although cetirizine significantly suppressed cytokine promotion of eosinophil survival, it was not as potent as dexamethasone. CONCLUSIONS: Although the in vitro concentration of cetirizine was required to be quite high, cetirizine may affect in vivo airway inflammation through its inhibition of IL-5-dependent eosinophil survival.
Adult↗
Cytokine profiles of stimulated blood lymphocytes in asthmatic and healthy adolescents across the school year.
T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-gamma (IFN-gamma), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-gamma:IL-4 and IFN-gamma:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation.
Adolescent↗
Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids.
BACKGROUND: Cysteinyl leukotriene release in association with airway inflammation is a feature of clinical asthma. The acute effects of montelukast (MK-0476), a potent, orally administered, specific cysteinyl leukotriene receptor antagonist, on airways obstruction was assessed in patients with mild to moderately severe asthma. METHODS: Twenty two asthmatic subjects were randomised to receive montelukast, 100 mg or 250 mg, or placebo in a double blind, three period, crossover trial. Ten of the patients were using concomitant inhaled corticosteroids. RESULTS: Montelukast increased the forced expiratory volume in one second (FEV1) from predose baseline values compared with placebo, the percentage point differences between montelukast and placebo being 8.6% (95% CI 3.6 to 13.6) and 8.5% (95% CI 3.5 to 13.5) for the 100 mg and 250 mg doses, respectively. CONCLUSION: Single oral doses of montelukast 100 mg and 250 mg produced significant increases in FEV1 irrespective of the concurrent use of inhaled corticosteroids in asthmatic subjects with airflow limitation.
Acetates↗
Synergistic activation of eosinophil superoxide anion generation by VCAM-1 and GM-CSF. Involvement of tyrosine kinase and protein kinase C.
During the development of allergic inflammation of asthma, eosinophils (EOS) are likely to interact with endothelial adhesion molecules, such as VCAM-1 and inflammatory cytokines, such as GM-CSF. To determine whether VCAM-1 and GM-CSF can interact to modify EOS superoxide anion (O2-) generation, peripheral blood EOS were incubated in either recombinant human (rh)-VCAM-1 or buffer (control)-coated 96-well plates in the presence or absence of 100 pM GM-CSF. VCAM-1 and GM-CSF acted synergistically to stimulate O2- generation which was significantly inhibited by either genistein, a tyrosine kinase inhibitor, or staurosporine, a protein kinase C inhibitor. These results indicate that interaction between VCAM-1 and GM-CSF can stimulate EOS function and its eventual contribution to the allergic inflammation process. Furthermore, our results demonstrate the involvement of tyrosine kinase and protein kinase C in this specific EOS activation.
Asthma↗
Detection of rhinovirus RNA in lower airway cells during experimentally induced infection.
Rhinovirus (RV) infections are presumed to be localized to the upper airway, yet can cause severe lower airway symptoms in children and adults with asthma. To test the hypothesis that rhinovirus infection of the upper airway may be associated with the presence of virus in lower airway cells, we used the techniques of reverse transcription-polymerase chain reaction (RT-PCR) and Southern blotting to detect RV RNA in lower airway cells from eight allergic volunteers experimentally infected with RV16. Bronchoscopy with bronchoalveolar lavage (BAL) was done 1 mo before, and 2 and 4 d after an experimental infection with RV16. All subjects developed cold symptoms, and infection was confirmed by culturing RV16 from nasal secretions. Rhinovirus RNA was detected in both nasal lavage and lower airway cells from all eight subjects 2 to 4 d after an experimental inoculation, but not in any of the precold specimens from either the nose or the lower airway. These findings suggest that RV can infect cells of the lower airway, and raise the possibility that such an effect can promote asthma exacerbations in the susceptible host through direct enhancement of local inflammation.
Adolescent↗