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Biomedical subjects

W W Busse

Publications and source records attributed to W W Busse.

At least 127 records · Page 7Linked to original sources
PubMed1994

The role of respiratory infections in airway hyperresponsiveness and asthma.

Viruses provoke symptoms of wheezing in many patients with asthma. Furthermore, there is evidence that viruses increase airway responsiveness in non-asthma patients. The mechanisms involved in these reactions are not clearly established, but evidence suggests that the ability of viruses to promote this bronchial responsiveness may be related to an upregulation of the allergic inflammatory reaction. This would explain why patients may be more prone to have a late asthmatic reaction.

Asthma↗
PubMed1994

A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects.

Many patients with asthma have increased wheezing with colds. We hypothesized that rhinovirus colds might increase asthma by augmenting airway allergic responses (histamine release and eosinophil influx) after antigen challenge. Seven allergic rhinitis patients and five normal volunteers were infected with rhinovirus type 16 (RV16) and evaluated by segmental bronchoprovocation and bronchoalveolar lavage. Segmental challenge with saline and antigen was performed 1 mo before infection, during the acute infection, and 1 mo after infection. Lavage was performed immediately and 48 h after antigen challenge. Data were analyzed by two-way analysis of variance, and a P value of < or = 0.05 was considered to be significant. All volunteers inoculated with RV16 developed an acute respiratory infection. BAL fluid obtained from allergic rhinitis subjects during the acute viral infection, and 1 mo after infection, showed the following significant RV16-associated changes after antigen challenge: (a) an enhanced release of histamine immediately after local antigen challenge; (b) persistent histamine leak 48 h afterwards; and (c) a greater recruitment of eosinophils to the airway 48 h after challenge. These changes were not seen in non-allergic volunteers infected with RV16 and challenged with antigen, nor in allergic volunteers repetitively challenged with antigen but not infected with RV16, nor in RV16 infected allergic volunteers sham challenged with saline. We conclude that rhinovirus upper respiratory infection significantly augments immediate and late allergic responses in the airways of allergic individuals after local antigen challenge. These data suggest that one mechanism of increased asthma during a cold is an accentuation of allergic responses in the airway which may then contribute to bronchial inflammation.

Bronchi↗
PubMed1994

Eosinophil eicosanoid relations in allergic inflammation of the airways.

Eosinophils are prominent features of allergic inflammation and can contribute to this process through release of inflammatory enzymes, granule-associated proteins, and leukotriene products. There is considerable interest in the fact that selected cytokines enhance eosinophil generation of leukotrienes. Therefore, future directions must include efforts to identify factors that regulate eosinophil synthesis of leukotrienes and therapeutic agents that might control these specific inflammatory responses.

Asthma↗
PubMed1994

Eosinophil as a therapeutic target in allergic disease.

The eosinophil appears to be a key cell in the development of active symptoms in both allergic diseases and asthma. Its involvement in inflammation seems to be mediated in part by release of its mediators ECP, MBP, EPO, and EDN. Therefore, the eosinophil and its inflammatory mediators would make ideal targets for pharmacological manipulation. In designing therapeutics to modify eosinophil participation, it will be helpful to keep the pharmacologic regulation as eosinophil-specific as possible. In this way, The function of other granulocytes is not affected and the patient is still able to fight infections.

Asthma↗
PubMed1994

Role of antihistamines in allergic disease.

Both first-generation and second-generation antihistamines effectively reduce symptoms of sneezing, rhinorrhea, and nasal pruritus in individuals with allergic disease. These agents act as competitive inhibitors of histamine (a principal mediator of the allergic response) at various target-organ sites. Although the classic, first-generation antihistamines are unable to halt the allergic reaction once it has begun, emerging evidence has suggested that newer, second-generation agents may interfere with the release of inflammatory mediators from mast cells or may inhibit eosinophil chemotaxis. These effects may confer additional clinical benefit. Also, the second-generation agents produce fewer adverse reactions, including a marked reduction in sedation. Contrary to previous recommendations, recent findings have suggested that antihistamines may not necessarily be contraindicated in patients who have both asthma and allergic rhinitis. A greater understanding of the mechanisms of action and clinical effects of both older-generation and newer-generation antihistamines should help define optimal therapeutic strategies in the future.

Histamine Antagonists↗
PubMed1993

Increased protein kinase C activity in low density eosinophils.

Eosinophil heterogeneity is expressed in cell density, membrane receptors and function. It has been observed that increases in some functional activities correlate with decreased sedimentation density in human eosinophils. However, the cellular mechanisms to explain the up-regulation of eosinophil function have not been fully explored. Protein kinase C (PKC) is an important family of enzymes mediating signal transduction for a wide variety of functions in many different cell types. Changes in the activity of PKC could explain some of the observed differences in function. In these experiments, PKC activity of human granulocyte lysate supernatants was measured as the phosphatidyl serine-dependent transfer of 32P from [gamma-32P]ATP to a protein substrate under conditions of maximal stimulation; a measure of activatable PKC concentration. We observed that the activity present in eosinophils (87.2 +/- 8.4 pmol PO4 incorporated into histone per minute per 10(6) cells, n = 30) was not significantly different from that of neutrophils assayed under the same conditions (91.5 +/- 5.6 U, n = 31) but the percent of total activity that was phosphatidyl serine dependent was greater in eosinophils (97 +/- 1% vs 81 +/- 1% for neutrophils, p = 0.001). Blood eosinophils isolated from low density Percoll fractions had a higher activity (120 +/- 16 U) than that found in the higher density cells from the same subjects (81 +/- 19 U, n = 9, p = 0.011). When eosinophils recovered from bronchoalveolar lavage (BAL) fluid after segmental Ag challenges were assayed, the PKC activity of BAL eosinophils was similar to that of blood-derived eosinophils of equal density and low density BAL eosinophil PKC tended to be equal to or greater than higher density cells. The beta isozyme of PKC but not the alpha or gamma was detected in eosinophils by Western blotting with isozyme-specific mAb. These data indicate that eosinophil PKC activity is primarily caused by the beta-isozyme, is related to cell density in blood-derived cells, and may have a relationship to cell function.

Blotting, Western↗
PubMed1993

Adhesion proteins on airway eosinophils in allergy and asthma.

Adhesion to, and interaction with, airway endothelium, interstitial matrix and epithelium during migration to the allergen-challenged airways of allergic rhinitis and asthma patients may account for the observed functional upregulation (priming) of airway eosinophils compared with corresponding blood eosinophils.

Allergens↗
PubMed1993

Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis.

BACKGROUND: The diagnosis of sinusitis is difficult and there are few controlled studies of customary therapies. In particular, the possible role of topical intranasal steroid as an adjunct to antibiotic treatment has not been evaluated. METHODS: The study was a multicenter, double-blind, randomized, parallel trial in which patients aged 14 years or older were recruited from allergy practices. All patients had maxillary sinusitis documented by radiographs. Treatment consisted of amoxicillin/clavulanate potassium 500 mg combined with nasal spray of either 100 micrograms flunisolide or placebo to each nostril three times a day for 3 weeks (phase I) followed by administration of flunisolide or placebo nasal spray alone three times a day for 4 weeks (phase II). RESULTS: Clinical symptoms and signs decreased significantly in both treatment groups during phase I (p < 0.01). There was a trend to greater improvement in the patients treated with flunisolide, but only the decrease in turbinate swelling/obstruction was statistically significant at the end of phase I when compared with placebo (p = 0.041). Patients' global assessment of overall effectiveness of treatment was higher for flunisolide than placebo after phase I (p = 0.007) and after phase II (p = 0.08). Maxillary sinus radiographs showed improvement in both treatment groups during phase I (p < 0.004) with somewhat greater regression of abnormal findings in patients treated with flunisolide after phase II (p = 0.066). However, 80% of radiographs were still abnormal at the end of phase I. All types of inflammatory cells were significantly decreased in nasal cytograms in patients treated with flunisolide in comparison with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of patients treated with flunisolide and 35% of those treated with placebo and tended to be more severe in the latter, although these differences were not statistically significant. Adverse events, mainly gastrointestinal symptoms and headache, were similar in both groups and more frequent in phase I than in phase II, (42 vs 15 patients); these side effects were probably due to the antibiotic. CONCLUSION: The addition of flunisolide topical nasal spray as an adjunct to antibiotic therapy was most effective in global evaluations, tended to improve symptoms, to decrease inflammatory cells in nasal cytograms, to normalize ultrasound scans, and to aid regression of radiographic abnormalities compared with placebo spray.

Administration, Inhalation↗
PubMed1993

Steroid-resistant asthma.

The treatment of patients with asthma that is resistant to corticosteroids represents a therapeutic challenge, because corticosteroids are the most potent and potentially effective medications for severe asthma. Recent investigations have identified several functional defects in mononuclear cells and T lymphocytes isolated from patients with corticosteroid-resistant asthma, including abnormalities in proliferation, activation, and cytokine production. The development of medications with immunomodulatory effects on specific cellular functions represents an exciting step for more efficacious treatment for such patients.

Asthma↗
PubMed1993

IL-5 is the predominant eosinophil-active cytokine in the antigen-induced pulmonary late-phase reaction.

The mechanism of airway eosinophilia during antigen-induced inflammation was investigated by measurement of eosinophil-active cytokines utilizing an eosinophil survival assay. In the first study, 4 patients with allergic rhinitis underwent segmental bronchoprovocation (SBP) with low, medium, and high doses of ragweed extract instilled into different bronchial subsegments; bronchoalveolar lavage (BAL) fluids were collected from each segment 12 min and 48 h after challenge. Eosinophil granule proteins and eosinophil survival activity were significantly elevated in the 48-h (late-phase) BAL fluids from these segments. Correlations were observed between the concentrations of eosinophil granule proteins and eosinophil survival activity (rs = 0.717 to 0.880, p < 0.001) in BAL fluids. Eosinophil survival activity was completely neutralized by anti-IL-5 monoclonal antibody in five of the seven 48-h samples tested representing three of the 4 patients. In the two remaining samples, eosinophil survival activity was only partially neutralized by either anti-IL-5 antibody or anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) but was completely neutralized by anti-IL-5 and anti-GM-CSF in combination. Subsequently, in the second study, 10 patients with allergic rhinitis were challenged by SBP with ragweed extract. Eosinophil survival activity was significantly elevated in the 48-h BAL fluids; this activity was partially neutralized by anti-IL-5 antibody about (48%) and completely neutralized by the combination of anti-IL-5 and anti-GM-CSF antibodies. These findings suggest that the eosinophil survival activity in the late inflammatory lesions following SBP with allergen is mainly associated with IL-5, with small contributions from GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Increased airway inflammation with segmental versus aerosol antigen challenge.

Airway inflammation is increasingly recognized as a pivotal component of asthma. Because allergens provoke bronchial constriction and inflammation in allergic subjects, bronchial antigen challenge has emerged as a powerful technique for evaluating mechanisms involved in this process. In this study, we compare whole lung antigen challenge (WLAC) with segmental bronchoprovocation (SBP) in eight allergic, non-asthmatic, non-smoking subjects, and evaluated the response by bronchoalveolar lavage (BAL) prior to, and 48 h after antigen challenge. Both challenge techniques evoked airway inflammation, manifest as an increase in total cells and eosinophils recovered by BAL, an increase in total protein concentration, and enhanced production of superoxide anion by airspace cells. The degree to which these changes occurred was significantly greater with SBP than WLAC, and only SBP evoked persistent measurable change in alveolar macrophage density and eosinophil granule protein concentrations. Moreover, although both techniques were associated with a comparable immediate fall in FEV1, only WLAC resulted in statistically significant persistent physiologic changes 48 h afterwards. We conclude that, as anticipated, SBP produces more intense airway inflammation in allergic subjects, does not result in late airway obstruction, and offers specific advantages in studying allergen-driven airway inflammation.

Adult↗
PubMed1993

Mechanism of airway inflammation in asthma.

Airway inflammation has emerged as an important contributor to mechanisms of asthma. Furthermore, the presence of airway inflammation is present even in the absence of severe symptoms. To study the mechanisms by which bronchial inflammation can occur in asthma, a number of models have been developed including the airway response to antigen in allergic subjects. The pattern that has emerged from such studies indicates prompt pulmonary mast-cell activation and the apparent initiation of an inflammatory response. This inflammatory response develops over hours and is important in the later and more persistent development of bronchial obstruction. The eosinophil is an important cell in this process as are proinflammatory cytokines generated from activated lung mononuclear cells. The consequence of this multiple cell, multiple proinflammatory product interaction is the establishment of a self-perpetuating, redundant process by which asthma severity increases.

Asthma↗
PubMed1993

Corticosteroid resistance in eosinophilic gastritis--relation to in vitro eosinophil survival and interleukin 5.

Eosinophilic gastritis is usually responsive to corticosteroid therapy. In some cases, large doses and protracted treatment are required. This report describes a case of eosinophilic gastritis that was partially corticosteroid resistant. To determine mechanisms that explain this patient's incomplete response to corticosteroid therapy, peripheral blood eosinophils and serum were isolated from the patient. We found the in vitro survival of the patient's eosinophils was prolonged. In addition, his serum both promoted in vitro eosinophil survival and nullified the survival inhibiting of effect of hydrocortisone (10 microM). Furthermore, antibody against interleukin 5 (IL5) partially inhibited the enhanced eosinophil survival produced by the patient's serum and completely blocked the decrease in survival resulting from hydrocortisone. These observations indicate that elevated circulating levels of IL5 may contribute to the peripheral eosinophilia and corticosteroid resistance in some patients with eosinophilic gastritis.

Adrenal Cortex Hormones↗
PubMed1992

Comparison of airway and blood eosinophil function after in vivo antigen challenge.

Eosinophils (EOS) are important effector cells in allergic diseases and asthma. However, functional characteristics of the EOS have been derived primarily from studies of blood cells, and it is unlikely that such assessments reflect events occurring in tissues or airways. To establish more precisely the function of airway EOS, segmental Ag challenge was used to elicit and isolate large numbers of these cells. Airway, as well as blood, EOS were isolated from allergic patients 48 h after segmental Ag challenge. Both blood and bronchoalveolar lavage (BAL) EOS were fractionated over Percoll density gradients; by using this protocol, three density-distinct populations of pure (>90%) EOS were obtained from BAL fluid (1.100, 1.095, and 1.090 g/ml) and one from blood (1.100 g/ml). The functions of these various populations were compared by measuring superoxide generation, adherence to collagen and endothelial cell monolayers, cell surface receptors, and in vitro survival. BAL EOS of all three densities had greater superoxide generation and adherence with FMLP activation than did corresponding blood EOS. In contrast, blood and airway EOS responded similarly to PMA. BAL EOS also had increased expression of CD11b/CD18 and HLA-DR. The intracellular calcium concentration ([Ca2+]i) was measured with the fluorescent marker indo-1/acetoxymethyl ester. FMLP caused a greater and more sustained increase in [Ca2+]i with BAL than blood EOS. EGTA blocked the sustained component of the [Ca2+]i response to FMLP. Our findings indicate that BAL EOS have an enhanced [Ca2+]i response to activation that may contribute to their functional up-regulation.

Adult↗
PubMed1992

Inhibition of eosinophil density change and leukotriene C4 generation by nedocromil sodium.

Nedocromil sodium (NS) has been shown to inhibit the late asthma response to inhaled antigen and to control symptoms in chronic asthma; in both processes the eosinophil is thought to be an important contributor. To understand the antiinflammatory actions of NS in asthma, its effects on three eosinophil functions were evaluated: (1) change in cell density during in vitro culture, (2) synthesis of leukotriene C4 (LTC4), and (3) generation of superoxide anion. In these studies normal density (greater than 1.095 gm/ml) purified human peripheral blood eosinophils were cultured for 24 hours in 50% conditioned medium from cow pulmonary arterial endothelial cells. After incubation, 45.2% +/- 8.0% of the eosinophils had a density less than 1.085 gm/ml. In the presence of NS (10 mumol/L), only 32.0% +/- 7.3% became less dense (p = 0.0393). In contrast, NS had no effect on changes in cell density after a 20-minute exposure of eosinophils to functional activators N-formyl-methionyl-leucyl-phenylalanine (0.1 mumol/L) or platelet activating factor (0.1 mumol/L). Furthermore, calcium ionophore-activated LTC4 secretion was found to be significantly inhibited by NS (3.8 +/- 0.6 ng/ml vs. 2.4 +/- 0.3 ng/ml with 1 mumol/L NS or 1.7 +/- 0.6 ng/ml with 10 mumol/L NS, p less than 0.025). However, NS did not significantly alter eosinophil superoxide anion generation. The effects of NS on eosinophil function suggest a mechanism by which this medication may be effective in asthma, particularly in the regulation of the late asthmatic response. Furthermore, the selective regulatory effects of NS may also provide insight into the biologic activities of eosinophils.

Adult↗
PubMed1992

Respiratory infections and asthma.

Airway responsiveness is increased during respiratory virus infections, both in subjects with asthma and without underlying pulmonary disease. Furthermore, the airway hyperresponsiveness is altered for a prolonged period of time, weeks or months after the viral illness has subsided. This article reviews the possible mechanisms of virus-associated airway hyperresponsiveness, including the complex interplay of IgE-dependent reactions, changes in autonomic nervous system function and inflammation, epithelial damage, effects of viruses on the cellular immune response, and enhanced late-phase response.

Adrenal Cortex Hormones↗