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Biomedical subjects

William W Busse

Publications and source records attributed to William W Busse.

At least 19 recordsLinked to original sources
PubMed2003

Rhinovirus-induced interferon-gamma and airway responsiveness in asthma.

The majority of asthma exacerbations are caused by respiratory infections, with rhinovirus (RV) being the most common virus. Recent evidence has suggested that decreased generation of IFN-gamma is associated with more severe colds and delayed elimination of virus. Whether the generation of IFN-gamma also has any relationship to general features of asthma severity has yet to be determined. To evaluate this hypothesis, peripheral blood mononuclear cells from 19 subjects with atopy and asthma were incubated with RV16 for 6 days to determine IFN-gamma and interleukin (IL)-5 production; these responses were then compared with measurements of airflow obstruction and airway responsiveness. RV16-induced IFN-gamma production correlated significantly with the methacholine PD (r = 0.50, p = 0.03), and the ratio of RV16-induced IFN-gamma:IL-5 correlated with % predicted FEV1 (r = 0.53, p = 0.02). In contrast, there were no significant associations between measures of asthma severity and RV-induced IL-5. These findings suggest that a cytokine imbalance with a deficient Th1 response to RV, but not a Th2 response, is associated with measures of asthma severity and support the concept that impaired antiviral responses may be associated with asthma severity.

Adolescent↗
PubMed2003

Oxidized low-density lipoprotein activates migration and degranulation of human granulocytes.

Oxidized low-density lipoprotein (oxLDL) has been reported as a major participant in the pathogenesis of atherosclerosis. We hypothesized that oxLDL can also interact with granulocytes during inflammatory airway diseases, such as asthma. To test the chemotactic effect of oxLDL, isolated human peripheral granulocytes were added to the upper chambers of Transwell filters and migration in response to oxLDL was determined. Cu+2-oxidized LDL stimulated neutrophil (23.4 +/- 3.2% for 100 microg/ml oxLDL versus 2.9 +/- 1.1% for buffer, P < 0.05) and eosinophil (19.3 +/- 3.5% versus 0.6 +/- 0.02% for buffer, P < 0.05) chemotaxis in a concentration-dependent manner. The magnitude of chemotaxis was dependent on the degree of LDL oxidation. Granulocyte transmigration across IL-1beta-activated human pulmonary microvascular endothelial cell monolayers was similarly stimulated by oxLDL. OxLDL activated significant degranulation of both neutrophils (100.9 +/- 9.8 versus 49.6 +/- 8.4 ng lactoferrin released/5 x 105 neutrophils for buffer, P < 0.05) and eosinophils (342 +/- 115.4 versus 85.8 +/- 30.4 ng eosinophil-derived neurotoxin/1 x 106 eosinophils for buffer, P < 0.05). Therefore, in vivo influx and oxidation of LDL may be an important mediator for the initiation of bronchial inflammation where granulocytes are recruited to the lung.

Adult↗
PubMed2003

Serum and low-density lipoprotein enhance interleukin-8 secretion by airway epithelial cells.

Viral respiratory infections rapidly increase vascular permeability, which leads to the transudation of serum proteins into airway secretions and tissues. To determine whether this process activates airway epithelial cells, bronchial epithelial cells were incubated with serum, and interleukin (IL)-8 secretion and gene expression were examined. As little as 0.1% serum significantly enhanced IL-8 secretion, and maximal secretion (65 +/- 4 ng/ml, 48 h) was observed with 10% serum. Low-density lipoprotein, but not albumin or immunoglobulin G, augmented bronchial epithelial IL-8 secretion, which was partially blocked by a monoclonal antibody specific for the low-density lipoprotein receptor. The IL-8-inducing activity of plasma was also augmented by clotting and platelet activation. Mechanistically, serum activated nuclear factor-kappaB and increased the stability and steady state levels of IL-8 mRNA. In summary, specific components of serum are potent activators of IL-8 mRNA and secretion, and the increased IL-8 production is likely to be a result of both increased transcription and mRNA stability. This effect may represent an innate mechanism for the recruitment of neutrophils to the airway in response to noxious stimuli, such as viral infections, that increase vascular permeability.

Blood Proteins↗
PubMed2003

Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial.

BACKGROUND: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established. METHODS: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat. FINDINGS: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively). INTERPRETATION: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

Administration, Topical↗
PubMed2003

Comparison of the effects of repetitive low-dose and single-dose antigen challenge on airway inflammation.

BACKGROUND: Airway allergen provocation provides a model to study allergic inflammation in relationship to pulmonary physiology. Allergen provocation is usually administered as a relatively large single-dose challenge that might not reflect a chronic, natural, low-dose airborne allergen exposure. OBJECTIVE: We sought to compare the magnitude, characteristic features, and kinetics of airway inflammation induced by means of repetitive low-dose antigen challenges with those factors induced by means of an equivalent single-dose allergen challenge in allergic asthma. METHODS: This was a 2-period crossover study. During separate phases, each subject was administered either a predetermined single-dose antigen challenge or 25% of that dose on each of 4 consecutive days. The airway response to allergen challenge was determined by means of measurement of pulmonary function and sputum features of inflammation, including eosinophil, eosinophil-derived neurotoxin, and fibronectin levels. RESULTS: Both models of antigen challenge caused significant and equivalent sputum eosinophilia. The immediate decrease in FEV(1) and the FEV(1)/forced vital capacity ratio and the increase in sputum eosinophilia, eosinophil-derived neurotoxin, and fibronectin levels occurred gradually over the first 3 low doses and then reached a plateau or tended to decrease with the fourth antigen exposure. CONCLUSION: Our data suggest that although the 2 challenge models had similar quantitative effects on lung function and sputum eosinophilia, the qualitative responses and kinetics of these changes were distinct. Repetitive low doses of antigen, as might mimic natural allergy exposure, produced an equivalent inflammatory response to the large single-dose challenge but with a smaller amount of antigen, suggesting that priming and accumulative effects might have occurred. Moreover, our limited data also suggest that immunologic tolerance might be induced by frequent challenges.

Adult↗
PubMed2003

Ligation of intercellular adhesion molecule 3 inhibits GM-CSF production by human eosinophils.

BACKGROUND: Intercellular adhesion molecule 3 (ICAM-3) has recently been identified on the surface of eosinophils. OBJECTIVE: The purpose of this study was to characterize ICAM-3 expression on eosinophils in response to cytokines and to determine whether ligand binding of ICAM-3 modulates inflammatory responses of eosinophils, as it does in other leukocytes. METHODS: To determine effects of ICAM-3 on eosinophil function, we isolated human eosinophils and used a monoclonal antibody directed against the epitope of ICAM-3 that binds to leukocyte-function antigen-1 to mimic binding of ICAM-3 and this natural ligand. We measured granulocyte-macrophage colony stimulating factor (GM-CSF) production by unstimulated eosinophils and eosinophils stimulated with ionomycin (1 micromol/L), both in the presence and absence of this anti-ICAM-3 antibody. RESULTS: We found that 99% of eosinophils expressed ICAM-3, regardless of whether allergic symptoms were present or absent. Expression of ICAM-3 was not enhanced by proinflammatory cytokines. Expression of ICAM-3 was reduced in apoptotic cells and in cells incubated with the combination of GM-CSF and tumor necrosis factor-alpha (n = 3). Antibody binding of ICAM-3, which mimics leukocyte-function antigen-1 binding, had no effect on baseline GM-CSF production but reduced by 80% the production of GM-CSF stimulated by ionomycin (control 1969 pg/mL +/- 1259 SD versus anti-ICAM-3 396 pg/mL +/- 207 SD, n = 8) and reduced GM-CSF mRNA content. CONCLUSIONS: ICAM-3 is highly expressed on the surface of human eosinophils, and downregulation of GM-CSF production by anti-ICAM-3 mAb suggests that ICAM-3 ligation may inhibit eosinophil inflammatory responses and survival.

Adult↗
PubMed2003

Mechanisms of asthma.

Airway inflammation is a key factor in the mechanisms of asthma. Articles published in the Journal of Allergy and Clinical Immunology this past year have highlighted the utility of investigative bronchoscopy with segmental antigen challenge and induced sputum analyses to evaluate features of airway inflammation in relationship to asthma severity. Peripheral blood cell generation of cytokines IFN-gamma (T(H)1) and IL-5 (T(H)2) was used to evaluate the relationship of the balance of T(H)1/T(H)2 cytokines to asthma persistence and severity in a 42-year, longitudinal study. Chemokines, including thymus and activation-regulated chemokine, are important to the regulation of inflammation and IgE synthesis. Their potential role in asthma has also been evaluated. Finally, albuterol (R)- and (S)-enantiomers may have distinct effects on airway relaxation and regulation of inflammation, suggesting the possibility that monoisomeric therapy has therapeutic advantages. The potential contribution of genetic factors and mechanisms to airway inflammation and remodeling also continues to be an area of intense investigation. During the past year a number of articles published in the Journal of Allergy and Clinical Immunology have identified and clarified potential genetic mechanisms in asthma. The contribution of genetics to asthma has been examined in a wide variety of studies, ranging from epidemiologic association and twin studies all the way to molecular analysis through microarray gene expression experiments.

Adenine↗
PubMed2003

A comparison of the airway response to segmental antigen bronchoprovocation in atopic asthma and allergic rhinitis.

BACKGROUND: Patients with allergic asthma and those with allergic rhinitis (without asthma) share many immunopathologic features but differ in the presence of lower airway symptoms in response to antigen. OBJECTIVES: We sought to compare the airway inflammatory response to antigen in patients with atopic asthma and allergic rhinitis. METHODS: Segmental bronchoprovocation with saline or ragweed antigen was performed in 9 patients with atopic asthma and 9 patients with allergic rhinitis without asthma. The antigen dose used in segmental bronchoprovocation was 10% of the dose that caused a 20% decrease in FEV1 in response to inhalation challenge. Bronchoalveolar lavage (BAL) was performed from the saline- and antigen-challenged segments at 5 minutes and 48 hours after challenge. BAL fluid was analyzed for cell count and differential, distribution of lymphocytes, and concentration of soluble factors (histamine, IL-5, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1, and fibronectin). In addition, BAL cells were cultured ex vivo, and IL-5, IFN-gamma, and IL-10 generation was measured. RESULTS: Antigen challenge led to similar patterns of cellular recruitment, mediator levels, and BAL cell cytokine generation in both groups; however, the dose of antigen required to promote comparable responses in the airway was significantly less in patients with asthma. CONCLUSION: These data suggest that the pattern of acute airway inflammation in response to allergen does not by itself explain antigen-induced lower airway obstruction and asthma symptoms. We speculate that other factors, such as increased airway sensitivity to allergen or preexisting airway injury and remodeling, might explain why patients with asthma and rhinitis differ in their clinical and physiologic response to antigen exposure.

Adult↗
PubMed2003

6. Asthma.

The increasing incidence and prevalence of asthma in many parts of the world continue to make 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 triggering factors including viral infections, allergen and irritant exposure, and exercise, among others, complicate both the acute and chronic treatment of asthma. Therapeutic intervention has focused on the appreciation that airway obstruction in asthma is composed of both bronchial smooth muscle spasm and variable degrees of airway inflammation characterized by edema, mucus secretion, and the influx of a variety of inflammatory cells. The presence of only partial reversibility of airflow obstruction in some patients indicates that structural remodeling of the airways may also occur over time. Choosing appropriate medications depends on the disease severity (intermittent, mild persistent, moderate persistent, severe persistent), extent of reversibility, both acutely and chronically, patterns of disease activity (exacerbations related to viruses, allergens, exercise, etc), and the age of onset (infancy, childhood, adulthood).

Allergens↗
PubMed2002

Double-stranded RNA induces the synthesis of specific chemokines by bronchial epithelial cells.

Virus-induced secretion of proinflammatory chemokines (e.g., regulated on activation, normal T cells expressed and secreted [RANTES], interleukin [IL]-8) by airway epithelial cells helps to initiate antiviral responses and airway inflammation by enhancing inflammatory cell recruitment. To define mechanisms for virus-induced chemokine secretion, monolayers of nontransformed bronchial epithelial cells were transfected or incubated with polydeoxyinosinic-deoxycytidylic acid (synthetic double-stranded [ds] RNA), rhinovirus dsRNA, or single-stranded RNA (ssRNA), and the secretion of selected chemokines was determined. Transfection or incubation with dsRNA, but not ssRNA, significantly enhanced secretion of RANTES and IL-8, but not eotaxin or macrophage inflammatory protein-1alpha. Mechanistically, dsRNA induced and activated dsRNA-dependent protein kinase (PKR), and activated nuclear factor-kappaB and p38 mitogen-activated protein kinase. Furthermore, the PKR inhibitor 2-aminopurine significantly blocked dsRNA-induced RANTES and IL-8 secretion, whereas the p38 mitogen-activated protein kinase inhibitor SB203580 suppressed dsRNA-induced IL-8, but not RANTES. These findings indicate that dsRNA selectively induce the secretion of chemokines such as IL-8 and RANTES, and implicate dsRNA-sensitive signaling proteins in this process. Moreover, these data suggest that this may be an important mechanism for the selective secretion of chemokines by viruses (e.g., rhinovirus, respiratory syncytial virus, influenza) that synthesize dsRNA during replication.

Bronchi↗
PubMed2002

Decreased expression of membrane IL-5 receptor alpha on human eosinophils: I. Loss of membrane IL-5 receptor alpha on airway eosinophils and increased soluble IL-5 receptor alpha in the airway after allergen challenge.

IL-5 is a key cytokine for eosinophil maturation, recruitment, activation, and possibly the development of inflammation in asthma. High concentrations of IL-5 are present in the airway after Ag challenge, but the responsiveness of airway eosinophils to IL-5 is not well characterized. The objectives of this study were to establish, following airway Ag challenge: 1) the expression of membrane (m)IL-5Ralpha on bronchoalveolar lavage (BAL) eosinophils; 2) the responsiveness of these cells to exogenous IL-5; and 3) the presence of soluble (s)IL-5Ralpha in BAL fluid. To accomplish these goals, blood and BAL eosinophils were obtained from atopic subjects 48 h after segmental bronchoprovocation with Ag. There was a striking reduction in mIL-5Ralpha on airway eosinophils compared with circulating cells. Furthermore, sIL-5Ralpha concentrations were elevated in BAL fluid, but steady state levels of sIL-5Ralpha mRNA were not increased in BAL compared with blood eosinophils. Finally, BAL eosinophils were refractory to IL-5 for ex vivo degranulation, suggesting that the reduction in mIL-5Ralpha on BAL eosinophils may regulate IL-5-mediated eosinophil functions. Together, the loss of mIL-5Ralpha, the presence of sIL-5Ralpha, and the blunted functional response (degranulation) of eosinophils to IL-5 suggest that when eosinophils are recruited to the airway, regulation of their functions becomes IL-5 independent. These observations provide a potential explanation for the inability of anti-IL-5 therapy to suppress airway hyperresponsiveness to inhaled Ag, despite a reduction in eosinophil recruitment.

Adult↗
PubMed2002

Decreased expression of membrane IL-5 receptor alpha on human eosinophils: II. IL-5 down-modulates its receptor via a proteinase-mediated process.

In the accompanying study, we demonstrated that following Ag challenge, membrane (m)IL-5Ralpha expression is attenuated on bronchoalveolar lavage eosinophils, soluble (s)IL-5Ralpha is detectable in BAL fluid in the absence of increased steady state levels of sIL-5Ralpha mRNA, and BAL eosinophils become refractory to IL-5 for ex vivo degranulation. We hypothesized that IL-5 regulates its receptor through proteolytic release of mIL-5Ralpha, which in turn contributes to the presence of sIL-5Ralpha. Purified human peripheral blood eosinophils were incubated with IL-5 under various conditions and in the presence of different pharmacological agents. A dose-dependent decrease in mIL-5Ralpha was accompanied by an increase in sIL-5Ralpha in the supernatant. IL-5 had no ligand-specific effect on mIL-5Ralpha or sIL-5Ralpha mRNA levels. The matrix metalloproteinase-specific inhibitors BB-94 and GM6001 and tissue inhibitor of metalloproteinase-3 partially inhibited IL-5-mediated loss of mIL-5Ralpha, suggesting that sIL-5Ralpha may be produced by proteolytic cleavage of mIL-5Ralpha. IL-5 transiently reduced surface expression of beta-chain, but had no effect on the expression of GM-CSFRalpha. Pretreatment of eosinophils with a dose of IL-5 that down-modulated mIL-5Ralpha rendered these cells unable to degranulate in response to further IL-5 stimulation, but they were fully responsive to GM-CSF. These findings suggest that IL-5-activated eosinophils may lose mIL-5Ralpha and release sIL-5Ralpha in vivo, which may limit IL-5-dependent inflammatory events in diseases such as asthma.

Cell Degranulation↗
PubMed2002

School examinations enhance airway inflammation to antigen challenge.

Psychological stress can lead to asthma exacerbations in some patients. It is our hypothesis that the stress effect can occur through an enhancement of allergic inflammatory response. To investigate this possibility, airway antigen challenge was evaluated in 20 college students with mild asthma during both a low-stress phase (midsemester or two weeks postfinal examination) and a stress phase (final examination week). Subjects completed questionnaires to assess psychological state and underwent inhaled antigen challenge. Sputum samples were collected before challenge, and six and 24 hours and seven days postchallenge. Leukocytes were counted and eosinophil-derived neurotoxin (EDN) was measured in sputum supernates. Sputum cells were cultured and stimulated ex vivo with phytohemagglutinin (10 microg/ml), and culture supernates were assayed for interleukin-5 (IL-5) and interferon-gamma by enzyme-linked immunosorbent assay. Sputum eosinophils and EDN levels significantly increased at six and 24 hours postchallenge and were enhanced during the stress phase (p < 0.01). IL-5 generation by sputum cells was also increased at 24 hours during stress and correlated with airway eosinophils (r(s) = 0.65, p < 0.05). Students' anxiety and depression scores were significantly higher during the examination period. Our findings suggest that stress associated with final examinations can act as a cofactor to increase eosinophilic airway inflammation to antigen challenge and thus may enhance asthma severity.

Administration, Inhalation↗
PubMed2002

Similar frequency of rhinovirus-infectible cells in upper and lower airway epithelium.

Rhinovirus (RV) infections can alter lower airway physiology and inflammation, yet the characteristics of RV replication in lower airway cells are incompletely understood. An RV serotype 16 (RV16)-specific monoclonal antibody was identified. Immunohistochemistry and an infectious center assay were used to quantitate the infectivity of RV16 in primary bronchial and adenoidal epithelial cells. The proportion of infectible epithelial cells increased with the inoculum but did not exceed 10%. Analysis of bronchial tissue samples infected ex vivo demonstrated a small subset of RV-infected cells in the epithelial layer. These data confirm previous reports that RV infects only a small subset of epithelial cells in upper airway tissues and indicate that lower airway epithelial cells have a similar susceptibility to RV infection. In confirming that RV can infect cells in the lower airway, these results suggest that lower airway dysfunction occurs through this mechanism in susceptible persons.

Adenoids↗
PubMed2002

Refractory asthma.

Treating patients with refractory asthma remains an ongoing challenge. Although most patients respond to large doses of systemic corticosteroid, the adverse effects associated with such a treatment limit its general use. Clinicians treating patients with refractory asthma must consider tapering systemic corticosteroid at every opportunity. Recent advances in the understanding of the pathogenesis of refractory asthma and corticosteroid resistance have fueled further study in the mechanisms of these processes and have prompted consideration of new treatment approaches. Unfortunately, most alternative approaches require more rigorous evidence to support their regular use.

Asthma↗
PubMed2002

Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis.

BACKGROUND: Mometasone furoate nasal spray (MFNS) 400 microg, twice daily, as adjunctive treatment with oral antibiotic significantly improved symptoms of recurrent rhinosinusitis. OBJECTIVE: To evaluate the effectiveness and safety of MFNS 200 microg, twice daily, and 400 microg, twice daily, compared with placebo as adjunctive treatment with oral antibiotic for acute rhinosinusitis. METHODS: In this multicenter, double-blind, placebo-controlled study, 967 outpatients with computed tomographic scan-confirmed moderate to severe rhinosinusitis received amoxicillin/clavulanate potassium (Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, for 21 days with adjunctive twice daily MFNS 200 microg, MFNS 400 microg, or placebo nasal spray. Patients recorded scores of six rhinosinusitis symptoms and any adverse events twice daily. Pre- and postcosyntropin-stimulation plasma cortisol levels were measured in a subset of patients at selected study sites. RESULTS: Treatment with MFNS 200 microg or 400 microg, twice daily, produced significantly greater improvements in total symptoms score (primary efficacy variable) day 1 to day 15 average (50% and 51%, respectively) than placebo (44%, P < or = 0.017). Both doses of MFNS produced significant total symptoms score improvement over placebo by day 4, and maintained efficacy over the entire 21-day study. Relief of individual symptoms showed a similar pattern. Both doses of MFNS were well tolerated, and adverse events were similar to that of placebo. Cosyntropin stimulation showed no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSIONS: As adjunctive therapy to oral antibiotic treatment, MFNS at doses of 200 microg or 400 microg, twice daily, was well tolerated and significantly more effective in reducing the symptoms of rhinosinusitis than antibiotic therapy alone.

Acute Disease↗
PubMed2002

Relationship of viral infections to wheezing illnesses and asthma.

Viral infections can influence both the development and the severity of asthma. In early life, viral infections can either increase or, remarkably, decrease the risk of subsequent asthma. In children and adults with existing asthma, viral respiratory infections frequently cause acute airway obstruction and wheezing. This article discusses the influence of viral infections on mechanisms of virus-induced airway inflammation in relationship to the development, persistence and severity of asthma.

Asthma↗