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Biomedical subjects

W W Busse

Publications and source records attributed to W W Busse.

At least 109 records · Page 6Linked to original sources
PubMed1996

The role of leukotrienes in asthma and allergic rhinitis.

The recent elucidation of the inflammatory responses underlying asthma and allergic rhinitis has stimulated the development of new anti-asthma treatments, including numerous antileukotriene agents. These agents, which represent a new direction in targeted therapy, either antagonize the leukotriene receptor (e.g. zafirlukast) or block the synthesis of leukotrienes (e.g. zileuton). They have been used in preclinical and clinical studies involving normal subjects and patients with asthma or allergic rhinitis. These studies have generally supported the putative role of leukotrienes in the mechanisms of asthma and allergic rhinitis. With respect to asthma, the leukotrienes also appear to function as potent mediators of bronchoconstriction. The above cited results indicate that antileukotriene agents offer incremental improvements in airway caliber and may also attenuate the inflammatory response. Because they are orally administered, they should have the additional benefit of increasing patient compliance relative to other currently available treatments. In their current form, however, they may not be expected to replace the mainstays of current therapy but to act rather, as adjuvant therapy. Patients with relatively mild asthma may be able to achieve efficacy with an antileukotriene agent plus as needed beta-adrenergic agonists; patients with more significant disease might use antileukotriene agents as a supplement to another anti-inflammatory agent, such as cromolyn, nedocromil, or corticosteroids. Studies of asthma patients have confirmed the ability of antileukotriene agents to attenuate asthma-associated bronchoconstriction. Antileukotriene agents appear to significantly attenuate aspirin-, allergen-, and exercise-induced asthma, as well as the signs and symptoms of nocturnal and chronic asthma; they may have efficacy in other inflammation-associated disorders such as allergic rhinitis as well.

Asthma↗
PubMed1996

Clinical aspects of anti-inflammatory therapy in asthma.

Anti-inflammatory therapy is now considered first-line treatment for mild to moderate asthma. Corticosteroids remain the most potent anti-inflammatory therapy available (although their mode of action is not clearly understood), and recent investigations suggest that earlier institution of anti-inflammatory therapy may be more beneficial than delayed therapy in newly diagnosed asthmatic patients. Inhaled corticosteroids have far fewer adverse effects than their oral counterparts; however, their risks must be carefully considered before use in mild asthma. These drugs can cause alterations in the hypothalamic-pituitary-adrenal axis, alter bone metabolism, and suppress growth in children. The potential long-term risk of these alterations remains the topic of much debate.

Administration, Inhalation↗
PubMed1995

Differential effects of granulocyte-macrophage colony-stimulating factor on eosinophil and neutrophil superoxide anion generation.

Eosinophils (EOS) are specifically recruited to sites of allergic inflammation and parasitic infection, while neutrophil (NEUT) influx predominates in bacterial infections. This biologic selectivity suggests that granulocytes may respond differently to inflammatory mediators such as granulocyte-macrophage-CSF (GM-CSF). To establish the mechanisms of the response of granulocytes to GM-CSF, isolated human peripheral blood EOS and NEUT were obtained from allergic rhinitis patients and incubated in vitro with this cytokine. Incubation with GM-CSF (10 or 100 pM) significantly enhanced FMLP-stimulated EOS superoxide anion (O2-) generation, LTC4 release, and adhesion to tissue culture plates. Both GM-CSF-enhanced EOS adhesion and O2- generation were inhibited by an anti-beta 2 (CD18) Ab suggesting that this beta 2 integrin was associated with increased cell function. In contrast, FMLP + cytochalasin B were required to demonstrate GM-CSF enhancement of NEUT O2- and LTB4 generation; GM-CSF had no effect on NEUT adhesion. Furthermore, GM-CSF augmentation of FMLP + cytochalasin B-activated NEUT O2- generation was not affected by anti-beta 2 Ab but was blocked by a 5-lipoxygenase-activating protein antagonist, BAY x 1005. Finally, 0.1 to 10 nM LTB4 mimicked the GM-CSF-priming effect on NEUT O2- generation, thus suggesting that the augmented NEUT respiratory burst was the result of LTB4 production and its effect on the NEUT. These data demonstrate that GM-CSF promotes EOS and NEUT O2- generation to FMLP via distinct mechanisms: enhanced adhesion of EOS vs autocrine-priming by enhanced LTB4 generation of NEUT.

Adult↗
PubMed1995

Eosinophil adhesion to vascular cell adhesion molecule-1 activates superoxide anion generation.

Adhesion to the adhesion protein, VCAM-1, on vascular endothelium is proposed to be an important factor in the selective accumulation of eosinophils at sites of allergic inflammation. To determine whether eosinophil adhesion to VCAM-1 is also associated with an alteration of eosinophil function, human peripheral blood eosinophils were isolated from allergic donors and incubated in VCAM-1-coated wells. Spontaneous adherence of isolated eosinophils to VCAM-1-coated wells was greater than cells incubated in FCS-treated control wells (38.0 +/- 1.6% vs 17.1 +/- 1.9%, n = 16, p < 0.0001). In addition, eosinophils incubated in VCAM-1-coated wells spontaneously generated modest but significant amounts of superoxide anion (O2-; 2.0 +/- 1.3 vs 00.5 +/- 0.5 nmol/5 x 10(5) cells, n = 9, p = 0.029). Moreover, when 100 nM FMLP was added to eosinophils in the presence of VCAM-1, significantly greater O2- generation occurred (7.2 +/- 0.9 vs 5.4 +/- 1.0 (FCS control) nmol/5 x 10(5) cells, n = 9, p = 0.009). Adhesion, as well as the spontaneous and enhanced O2- generation to FMLP activation, was blocked by the monoclonal anti-alpha 4 integrin Ab, HP 1/2, implying involvement of an alpha 4 integrin-VCAM-1 interaction. In contrast, the anti-CD18 mAb, L130, inhibited the spontaneous and enhanced O2- generation to FMLP without affecting adhesion, suggesting an involvement of CD18 molecule(s) only in VCAM-1-enhanced respiratory burst. Finally, 1 microM genistein, a tyrosine kinase inhibitor suppressed the VCAM-1-enhancing effect on eosinophil O2- generation and VCAM-1-induced tyrosine phosphorylation, suggesting a role for tyrosine phosphorylation in this eosinophil functional up-regulation. Our observations suggest that eosinophil adhesion to VCAM-1 may be an important step in determining the eventual functional activity of these cells as they migrate from the circulation to the airways and contribute to the allergic inflammatory process.

Adult↗
PubMed1995

Effect of interleukin-5 and granulocyte-macrophage colony stimulating factor on in vitro eosinophil function: comparison with airway eosinophils.

Eosinophils are hypothesized to be crucial in the development of allergic airway inflammation; however, the actual mechanisms that determine their inflammatory activity are still largely undefined. To investigate the factors that regulate eosinophil function in allergic airway disease, we have previously used segmental bronchoprovocation with allergen to study ex vivo eosinophil function. To determine whether the functional changes associated with airway eosinophils obtained by bronchoalveolar lavage 48 hours after antigen challenge are caused by exposure to airway-generated cytokines, normodense blood eosinophils were cultured in vitro with recombinant human interleukin-5 (IL-5) or granulocyte-macrophage colony stimulating factor (GM-CSF). The effect of cytokine exposure was then evaluated on selected cell functions. In vitro incubation with these cytokines for 24 hours significantly increased eosinophil membrane expression of CD18 and CD11b compared with culture in medium alone or eosinophils obtained by bronchoalveolar lavage. N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide anion generation was slightly but significantly enhanced by incubation with IL-5 but not with GM-CSF. In addition, spontaneous adhesion to human umbilical vein endothelial cell monolayers was increased after exposure to both IL-5 and GM-CSF. However, activated adhesion was enhanced only by culture with IL-5 and stimulation with N-formyl-methionyl-leucyl-phenylalanine. The magnitude of functional changes after in vitro preincubation of eosinophils with these cytokines did not achieve levels of superoxide anion and adhesion noted with airway eosinophils obtained after segmental bronchoprovocation with allergen. These observations raise the possibility that the contribution of IL-5 and GM-CSF to phenotypic changes of airway eosinophils is principally to enhance survival and expression of adhesion proteins. These data also suggest that, in addition to the generation of proinflammatory cytokines, other factors contribute to phenotypic changes in eosinophils as they migrate from the blood to the airway.

Blood Cells↗
PubMed1995

Viral infections in humans.

Viral respiratory infections can increase asthma symptoms in many patients. Although the mechanisms of these effects are not fully established, there is evidence that respiratory viruses can promote some components of allergic inflammation. In this regard, there is evidence that rhinovirus respiratory infections can lead to the development of late allergic reactions to inhaled allergen. This change in response to inhaled allergen supports the possibility that some respiratory infection will promote bronchial inflammation and may be a factor for increased wheezing with respiratory infection.

Allergens↗
PubMed1995

Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products.

The role of T cells in human allergic inflammation is just beginning to be understood. However, the data presented indicate how the T cell may be a pivotal cell to direct features of allergic inflammation in asthma, how the T cell may be able to transfer hyperresponsiveness, which is a feature of bronchial asthma, what some of the genetic factors are that may determine this process, and how an important precipitant of asthma, viral respiratory infections, may participate in this process. Its cells are isolated from patients with asthma and studied for their ability to generate proinflammatory failure. An expanded understanding of the chronic, persistent nature of asthma will become apparent.

Animals↗
PubMed1995

Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life.

This study examined the ability of fluticasone propionate aerosol to reduce oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated for 16 wk with placebo or fluticasone propionate aerosol (750 or 1,000 micrograms twice daily). Their dosage of oral prednisone was adjusted weekly according to predetermined criteria. A total of 69% and 88% of patients treated with fluticasone propionate 750 and 1,000 micrograms twice daily, respectively, compared with 3% of placebo-treated patients used no prednisone by the end of the study. In the fluticasone propionate groups, FEV1 and peak expiratory flow rates at the last evaluable visit/date improved and the number of night awakenings and symptomatic albuterol use declined relative to placebo values (p < 0.05). Patient-rated asthma symptoms improved in the groups receiving fluticasone propionate but not in the placebo group (p < 0.005). Fluticasone propionate aerosol was well-tolerated, and it improved some dimensions of health-related quality of life measured using a standard patient survey. Fluticasone propionate aerosol (750 or 1,000 micrograms twice daily) effectively and safely allowed most asthmatics dependent on oral corticosteroids to reduce or eliminate oral prednisone use while improving pulmonary function and quality of life.

Administration, Inhalation↗
PubMed1995

Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma.

Airflow obstruction can have a circadian pattern with nocturnal worsening. Airway inflammation is a cardinal feature of asthma, and it has been shown to increase at night in association with the decline in pulmonary function. Although the mechanisms regulating enhanced airway inflammation in asthma at night have yet to be ascertained, we hypothesized that circadian variation in cytokine expression or production is an important factor in the development of nocturnal airflow limitation. To investigate this possibility, spirometry and bronchoscopy were performed; the bronchoalveolar lavage (BAL) fluid obtained at 4:00 A.M. and at 4:00 P.M. were measured for IL-1 beta in asthmatics with (n = 5) and without (n = 9) nocturnal asthma. In addition, the activity of IL-3, IL-5, and GM-CSF was measured using a biologic assay (eosinophil survival-enhancing activity). BAL fluid concentrations of IL-1 beta were significantly greater at 4:00 A.M. than at 4:00 P.M. (1.14 +/- 0.6 versus 0.7 +/- 0.6 pg/ml; p = 0.05) in asthmatics with nocturnal airflow obstruction. Moreover, IL-1 beta levels at 4:00 A.M. tended to be higher in subjects with nocturnal asthma than in those without nighttime airflow reduction (1.14 +/- 0.6 versus 0.3 +/- 0.4 pg/ml; p = 0.1). On the other hand, eosinophil survival-enhancing activity in BAL fluid, which is usually associated with IL-3, IL-5, or GM-CSF, was not detected in relationship to nocturnal asthma. Because IL-1 beta can activate air-space cells, particularly alveolar macrophages, we propose that an increased release of this cytokine is a significant contributor to nocturnal airway inflammation and obstruction in asthma.

Adolescent↗
PubMed1995

The effects of rhinovirus infections on allergic airway responses.

Although it has long been recognized that the common cold is a potent trigger for symptoms of asthma, the mechanisms underlying the association between upper respiratory infection and increased lower airway obstruction remain obscure. The use of experimental infection of volunteers with or without respiratory allergies has enabled direct comparisons of common cold symptoms in these two groups. Furthermore, techniques such as bronchoalveolar lavage and segmental antigen challenge have been used to directly sample lower airway fluids and tissues during acute viral infection. This review summarizes the findings of studies examining the separate and combined effects of rhinovirus infection and allergen exposure on airway physiology and inflammation.

Asthma↗
PubMed1995

Adhesion of activated eosinophils to respiratory epithelial cells is enhanced by tumor necrosis factor-alpha and interleukin-1 beta.

Eosinophilic infiltration and damage to airway epithelium are characteristic features of asthma. To assess possible interactions between eosinophils and airway epithelium, Percoll-purified human peripheral blood eosinophils were evaluated for their ability to adhere to respiratory epithelial cell (REC) cultures. REC (an immortalized cell line, A549, and primary bronchial epithelial cells) were grown in 96-well tissue culture plates, treated with proinflammatory cytokines (TNF-alpha or IL-1 beta), and eosinophil adhesion to these tissues was determined. Cytokine treatment of the REC cultures significantly increased expression of intercellular adhesion molecule-1 (ICAM-1) (P < 0.01). Eosinophils demonstrated a variable baseline adhesion to untreated REC which was then significantly increased following activation with phorbol myristate acetate (PMA) (P < 0.01). Furthermore, treatment of REC monolayers with TNF-alpha or IL-1 beta significantly increased adhesion of PMA-stimulated eosinophils (P < 0.01). To delineate the adhesion proteins involved in the cell-cell interactions, assays were performed in the presence of specific blocking monoclonal antibodies to eosinophil CD18, CD11a, or CD11b, and REC ICAM-1 molecules. Blocking antibodies to ICAM-1 had no significant effect on levels of eosinophil adhesion. In contrast, antibodies to CD18, CD11a, and CD11b significantly decreased (P < 0.01) eosinophil adhesion, thus demonstrating pivotal roles for the CD11/CD18 (beta 2) integrins, but not necessarily for ICAM-1, in interactions between the REC and eosinophils. These data demonstrate that TNF-alpha and IL-1 beta increase eosinophil adhesion to human respiratory epithelial cell cultures by induction of ligands recognized by eosinophil beta 2 integrins.

Asthma↗
PubMed1995

Inflammation and asthma.

There is little doubt that chronic asthma represents a unique inflammatory process in which the airway has become the target. Observations that were originally made nearly 100 years ago have been borne out through the use of animal models and technologically sophisticated techniques that allow experimentation on isolated regions of the human bronchial tree. It is also apparent that the pathophysiologic processes responsible for the airway changes observed in asthma are more complex than those presented in this discussion. Neurologic, endocrine, and perhaps even psychologic factors may be involved in the genesis or promulgation of the asthmatic response. Experiments of nature, such as the LAD, provide valuable insights as to the elements necessary to mount an inflammatory response. The recent availability of genetically altered animals lacking genes for certain cytokines and growth factors, so-called "knock-out" mice, may similarly prove useful in the elucidation of the role of individual factors to the overall inflammatory cascade. Further understanding of the mechanism of the asthmatic inflammatory response will bring us closer to the discovery of new therapies designed to treat the causes of asthma, rather than palliate the symptoms.

Asthma↗
PubMed1994

NIH conference. Asthma.

Asthma is characterized by inflammation, reversible airway obstruction, and increased airway responsiveness to various stimuli. It has received wide public attention in recent years because of increasing morbidity and deaths, particularly among black persons. The important role of inflammation in the immunopathogenesis of asthma has led to a newer therapeutic approach directed at interrupting this inflammatory process. Among immune regulatory pathways involved in asthma pathogenesis, two lymphokines appear to be particularly important in controlling IgE production. Interleukin-4 is required for IgE production; without it, IgE production is inhibited. Interferon-gamma can diminish cell priming for interleukin-4 production. Thus, the interplay of these two cytokines will determine whether cells that can make interleukin-4 will be produced and, therefore, whether IgE will be produced in response to allergic stimuli. Further, in response to appropriate stimuli, mast cells and eosinophils are attracted to airways and release cytokines, lipid mediators, and preformed substances that cause inflammation. Modern asthma treatment is directed at interrupting this inflammatory process and places a much greater emphasis on use of anti-inflammatory agents, such as aerosolized or parenteral corticosteroids, and on non-steroidal anti-inflammatory agents, such as cromolyn sodium and nedocromil sodium. Research advances without therapeutic application, however, limit success. Projects such as the National Institute of Allergy and Infectious Diseases' National Cooperative Inner-City Asthma Study, which is directed toward underserved populations, are intended to identify more clearly the factors responsible for increasing morbidity and to develop appropriate therapeutic interventions.

Asthma↗
PubMed1994

Prolonged effect of inhaled salmeterol against exercise-induced bronchospasm.

Physical exercise is a common trigger for bronchial asthma. We evaluated the preventive effect on exercise-induced bronchospasm (EIB) of a single 42 micrograms dose of salmeterol, a uniquely long-acting inhaled bronchodilator, and compared salmeterol with 180 micrograms albuterol in two independent, randomized, double-blind, placebo-controlled studies involving 161 subjects. Three exercise challenges were conducted over 12 h, and bronchoconstriction following the serial challenges was assessed as change in FEV1 compared with predose values. The mean maximal percentage decrease in FEV1 after the three exercise challenges was 5% at 0.5 h, 8% at 5.5 h, and 13% at 11.5 h postdose in the salmeterol group compared with 7, 25, and 27%, respectively, in the albuterol group and 27, 27, and 26%, respectively, in the placebo group (p < 0.001, overall treatment difference). Albuterol provided complete protection against EIB (defined as < 10% decrease in FEV1 compared with predose values) only after the first exercise challenge, but salmeterol continued to provide complete protection in the majority of subjects after each exercise challenge: 80% (44 of 55) at 0.5 h, 70% (37 of 53) at 5.5 h, and 55% (29 of 53) at 11.5 h. Electrocardiographic monitoring revealed no clinically significant changes in any treatment group 15 and 30 min following each exercise challenge. In summary, these data demonstrate that salmeterol is effective against EIB and that a single 42 micrograms dose can prevent EIB for up to 12 h.

Administration, Inhalation↗
PubMed1994

Treatment regimen and side effects of treatment measures.

The severity of asthma can be judged by many features, including the need for medication and associated side effects. Since asthma has both acute and chronic characteristics, therapeutic regimens should be valuable as an instrument to define disease severity and the consequence of intervention. However, because of the variability of asthma severity within each patient, medication quantitation as an index of asthma severity is not without difficulty and limitation. Furthermore, the philosophy of asthma therapy has undergone changes over the past decade. Previously, anti-inflammatory therapy was reserved for only the most severely ill patients. Now, inflammation is recognized as a critical component of asthma, and all patients with active asthma (other than mild symptoms) are recommended to use anti-inflammatory therapy. Although there is little published experience with treatment regimens as an index of disease severity, those that have been used have found validity and reproducibility with this approach. In this paper, a scoring approach to medication use is recommended. Medication is classified into bronchodilator (beta-agonists, theophylline, and anticholinergic) or anti-inflammatory (corticosteroid and cromolyn sodium). Medication scores are given on either a per-use or a new-dosage basis. Furthermore, the eight medications are stratified according to potency (i.e., inhaled corticosteroid < oral corticosteroid < parenteral corticosteroid). From this approach, the severity of an individual patient's asthma can be quantitated, and this value can serve as one instrument to assess disease severity.

Algorithms↗