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Biomedical subjects

W W Busse

Publications and source records attributed to W W Busse.

At least 145 records · Page 8Linked to original sources
PubMed1992

Characteristics of peripheral blood eosinophils in patients with nocturnal asthma.

A number of mechanisms have been proposed to explain nocturnal exacerbations of asthma including circadian patterns in circulating cortisol and catecholamines. These factors may influence airway smooth muscle tone and circulating eosinophil characteristics and function. Because recent evidence has indicated that eosinophils contribute to airway inflammation and the severity of asthma, we evaluated the relationship among peripheral blood eosinophils, their density distribution, and the appearance of nocturnal asthma. Fifteen patients with asthma were evaluated. Spirometry (FEV1 and FVC) was determined at 0400 and 1600, and the number and density distribution of peripheral blood eosinophils were determined. Five patients had nocturnal asthma, defined as a 15% or greater fall in FEV1 at 0400 versus 1600. The patients with nocturnal asthma had greater numbers of eosinophils (cells x 10(6)/ml) at 0400 (0.845 +/- 0.13 versus 0.351 +/- 0.03) and 1600 (0.651 +/- 0.18 versus 0.319 +/- 0.07) and a greater circadian variation with peak eosinophilia at 0400. Furthermore, we found a significant circadian increase in low-density eosinophils (as determined by Percoll density gradient centrifugation) at 0400, but only in patients with nocturnal asthma. These observations suggest that a circadian variation in low density eosinophils may contribute to nocturnal exacerbations of asthma.

Adult↗
PubMed1992

Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma.

The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD4 receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD4 receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta 2-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV1 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV1) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV1 above baseline, 20 min after the start of the MK-571 infusion, was 22 +/- 3.9% compared with 1.3 +/- 2.3% for placebo (mean +/- SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Enhanced production of oxygen radicals in nocturnal asthma.

Although the mechanisms of nocturnal worsening of pulmonary function in asthmatics have not been entirely established, airway inflammation is felt to be a major factor in disease severity. Consequently, to determine whether changes in bronchoalveolar lavage (BAL) fluid cellular components and their functions are related to nocturnal airway obstruction, we performed BAL at 4:00 A.M. and at 4:00 P.M. in asthma subjects with (n = 5) and without (n = 10) nocturnal asthma. No significant changes were observed from 4:00 P.M. to 4:00 A.M. in the concentration of total cells or the percentage or concentration of eosinophils or neutrophils in BAL fluid from subjects with or without nocturnal asthma. However, superoxide anion generation by air-space cells from subjects with nocturnal asthma was significantly greater at 4:00 A.M. than at 4:00 P.M. (6.9 +/- 1.7 versus 1.8 +/- 0.5 nmol/500K cells/h, p less than 0.05). Moreover, superoxide production at 4:00 A.M. was greater in subjects with than in those without nocturnal asthma (6.9 +/- 1.7 versus 2.2 +/- 0.6, p less than 0.02). Furthermore, in our group of asthmatics, the change in generation of superoxide anion from 4:00 P.M. to 4:00 A.M. was significantly correlated with the change in FEV1 (r = -0.71, p less than 0.01). We conclude that the development of nocturnal airway obstruction in asthma is associated with enhanced production of oxygen radicals by air-space cells. Because oxygen radicals can cause airway injury and thus enhance bronchial obstruction, it is possible that the release of these reactive compounds is causally associated with nocturnal asthma.

Adult↗
PubMed1992

Platelet-activating factor primes human eosinophil generation of superoxide.

Platelet-activating factor (PAF) is a potent inflammatory mediator that can cause airway obstruction and hyperresponsiveness; these processes are also associated with pulmonary eosinophilia, suggesting a link between these two events. Thus, PAF's interaction with eosinophils may provide a mechanism for airway damage. However, direct in vitro activation of eosinophils by PAF requires concentrations that are likely higher than those achieved in vivo. As a result, we investigated whether lower, more physiologic concentrations of PAF could prime eosinophils for subsequent activation to another receptor-stimulated factor, in this case formylmethionylleucylphenylalanine (FMLP). To test this hypothesis, eosinophils were preincubated (1 and 15 min) with low concentrations of PAF (1 x 10(-8) and 1 x 10(-10) M); this exposure to PAF resulted in enhanced generation of superoxide anion to FMLP stimulation. Moreover, similar concentrations of PAF decreased eosinophil density and increased expression of cell surface CR3 receptors. Finally, low, nonactivating concentrations of PAF (1 x 10(-10) to 1 x 10(-8) M) caused transient increases in eosinophil cytosolic free Ca2+ concentrations. Collectively, these responses are consistent with the hypothesis that short-term exposure to low concentrations of PAF primes eosinophils to cause an enhanced inflammatory response upon subsequent activation to another receptor agonist. The consequences of this PAF-associated phenomenon can produce an enhanced inflammatory response and airway injury.

Adult↗
PubMed1992

The effect of T-cell depletion on enhanced basophil histamine release after in vitro incubation with live influenza A virus.

A number of mechanisms participate in virus-induced asthma. Previously, we described enhanced basophil histamine release (HR) during an experimentally induced rhinovirus infection and after in vitro incubation of peripheral blood mononuclear cells (PBMC) with influenza virus. This study extends our previous observations and examines the effect of influenza A virus on basophil leukotriene C4 (LTC4) release as well as the effect of T-cell depletion on virus-enhanced basophil HR. PBMC were isolated from ragweed-allergic subjects and incubated with live influenza A virus or control medium (allantoic fluid). After incubation with influenza A, ragweed antigen (AgE) stimulated LTC4 and HR were enhanced (P less than 0.05). To further define the role of T cells in virus-enhanced basophil secretion, PBMC were isolated and divided into two aliquots. In one aliquot, T cells were removed by magnetic bead separation of mouse monoclonal anti-CD3-coated lymphocytes. T-cell-depleted and nontreated PBMC suspensions were incubated with influenza A or control medium, collected, and challenged with AgE to release histamine. Basophil HR was enhanced in the virus-treated group of PBMC that had not undergone T-cell depletion. In contrast, virus incubation did not enhance HR in the T-cell-depleted fraction. Finally, preliminary analysis of the supernate from virus-treated leukocytes indicates the presence of interferon-gamma. These findings suggest that T cells, and their cytokine products, play an integral role in the process by which viruses enhance basophil HR.

Adult↗
PubMed1992

Eosinophils in asthma.

Eosinophils, a prominent feature of asthma, are found in increased numbers in the circulation and sputum, usually in relation to the severity of asthma. As a consequence of these clinical observations, investigators now speculate that the eosinophil has a central role in the pathogenesis of asthma. Recent evidence has begun to confirm these speculations. The allergic reaction of the airway to antigen and the development of the late asthmatic reaction have provided a clinical model to study asthma and the contribution of eosinophils to bronchial reactivity. In the late asthmatic reaction, airway eosinophilia occurs. Through a series of independent observations, the following eosinophil-related events have been noted with the development of late asthmatic reactions. With either laboratory or natural exposure to antigen, eosinophilic chemotactic factors are released. Although the sources of eosinophil chemotaxis are multicellular, this is an early step in the attraction of eosinophils to the airway. As this process is initiated, a series of events occurs to cause eosinophils to arrive in the airway and promote obstruction, injury, and bronchial hyperresponsiveness. These steps include eosinophil migration through the vascular endothelium, upregulation of eosinophils (characterized by a change in cell density), adhesion of eosinophils to airway epithelium, and release of eosinophil toxic products. This presentation will review some of the eosinophil-dependent factors that can cause asthma. Furthermore, the eosinophil may be a good target for future therapeutic interventions.

Animals↗
PubMed1991

The effect of platelet-activating factor on the generation of superoxide anion in human eosinophils and neutrophils.

The precise role of platelet-activating factor (PAF) in asthma has yet to be established. Nonetheless, the potential relationship between PAF and asthma appears to include the eosinophil (EOS) as an important link. Thus, to evaluate the effect of PAF on leukocyte-dependent inflammation, purified populations of human blood EOSs and neutrophils were isolated from the same subject. The two granulocyte populations were then incubated with PAF, and superoxide anion (O2-) generation was measured by reduction of cytochrome c in a microassay system. Both granulocyte cell types generated O2- when they were incubated with PAF. However, the generation of O2- was 3.4 times greater with EOSs (9.8 +/- 1.5 nmole of cytochrome c reduced per 5 x 10(5) cells) than neutrophils (2.9 +/- 0.4 nmole of cytochrome c reduced per 5 x 10(5) cells; p less than 0.0001). When the effect of PAF on [Ca++]i was measured with the fluorescent label, Indo-1, PAF caused similar increases in cellular fluorescence in both neutrophils and EOSs, but the increase in [Ca++]i of neutrophils occurred with lower concentrations of PAF. Furthermore, when similar experiments were conducted in the presence of an extracellular calcium chelator, ethylene glycol-bis-(beta-aminoethylether)-N,N,N',N'-tetraacetic acid, there was partial suppression in both the cellular fluorescence and O2- generation to PAF; this suggests that full expression of EOS generation of O2- by PAF requires both intracellular mobilization and a transmembrane influx of Ca++. Our data indicate that PAF can stimulate leukocyte O2- generation, but this response is greater in the EOS than the neutrophil. Therefore, our findings support the observation that the EOS is more responsive to PAF activation than other granulocytes and that this difference may contribute to participation of PAF in asthma.

Adult↗
PubMed1991

Viral infections and allergic disease.

Respiratory viruses have profound effect on airway function and the development of allergic reactions. We are particularly interested in the ability of respiratory viruses to promote the development of the inflammatory LAR. Present evidence suggests that the virus effects on LAR are multi-factorial including changes in inflammatory cell mediator release and the tissue-injurious properties of leukocytes. The end-result of these changes is reflected in the development of the late-phase allergic reaction. When this occurs in the airways, airway obstruction and reactivity will be greater. Uncovering the mechanisms of these effects will lead to a greater understanding of asthma and its pathogenesis.

Asthma↗
PubMed1991

The role of eosinophils in the pathophysiology of asthma.

From current information, a number of conclusions can be drawn. Antigen activation of the allergic reaction in the airways is associated with an immediate rise in mast cell derived mediators, including histamine and tryptase. Associated with antigen activation of the allergic reaction is recruitment of eosinophils to the airways. This can best be seen in the airway lavage 48 hours after challenge with antigen. An increased presence of eosinophils suggests that they are an important contributor to the late allergic reaction and may be one of the major constituents in the development of bronchial inflammation. Although many factors participate in the late allergic inflammatory response, eosinophil-derived proteins are known to cause airway injury. Regulation of eosinophils in this process is not clearly established; however, our findings of increased IL-5 in relationship to the presence of eosinophils and their granular proteins suggests that this cytokine may be an important modulator of eosinophil function and activation following allergen challenge. However, much remains unknown in understanding bronchial inflammation and the eosinophil's role in the process. In conclusion, the eosinophil is a major cellular participant in late phase allergic airway disease. Its presence and known functions suggest that the eosinophil is a significant cellular factor in the development of allergic airways disease in asthma. Further advances in this area will follow continued studies, particularly those which involve biopsy and correlation with airway physiology.

Animals↗
PubMed1991

The role of leukotriene antagonists and inhibitors in the treatment of airway disease.

Since the early recognition that leukotrienes are generated in response to allergen exposure, a role for these multipurpose mediators has been sought. The pharmacologic actions of the leukotrienes and their cell sources were strong evidence that they should contribute to allergic airway disease. That promise is now being fulfilled. Potent leukotriene receptor antagonists and enzyme inhibitors of leukotriene generation are now being investigated. With the availability of these new compounds, not only will greater insight to leukotrienes in asthma become apparent, but possibly newer, more effective therapeutics. Of additional interest and relevance is the potential role of leukotrienes in other nonrespiratory inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. Therefore, the role of leukotrienes in inflammation is not limited to the respiratory system but are more universal in their ability to cause tissue injury. Consequently, studies that have shown benefit from inhibition of leukotriene synthesis and antagonism of the LTD4 receptor in respiratory diseases are suggestive that such an approach will also be beneficial in other inflammatory diseases. For example, a study of 72 patients with A-64077 (zileuton) has demonstrated that 5-lipoxygenase inhibitors are efficacious in the treatment of inflammatory bowel disease. Therefore, the contribution of leukotrienes to inflammation is likely to be a global phenomenon, and the introduction of leukotriene antagonists and 5-lipoxygenase inhibitors may represent the beginning of a new era for the treatment of many inflammatory diseases.

Allergens↗
PubMed1991

Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with increased airway obstruction.

Bronchoalveolar lavage (BAL) fluid was evaluated for histamine and tryptase levels in 61 samples (46 samples from 24 atopic asthmatics, seven samples from seven patients with allergic rhinitis, and eight samples from eight normal volunteers). Asthmatics and patients with allergic rhinitis had significantly higher BAL histamine than did normal subjects (169 +/- 22, 141 +/- 23, 42 +/- 6 pg/ml, respectively; p less than 0.05, both comparisons). BAL fluid tryptase levels were also higher in asthmatics and patients with allergic rhinitis than in normal subjects (0.36 +/- 0.03, 0.38 +/- 0.05, 0.23 +/- 0.04 ng/ml, respectively; p less than 0.05, both comparisons); however, levels of tryptase and histamine in BAL were not correlated (r = -0.03 in the group as a whole, r = -0.12 in the asthmatic group). BAL concentration of histamine correlated inversely with FEV1 percent predicted in the asthmatic group (r = -0.44, p less than 0.005). Asthmatics with high BAL fluid histamine (greater than or equal to 100 pg/ml, n = 23) had lower FEV1 percent predicted (80 +/- 3% versus 96 +/- 3%, p = 0.0005), lower FEV1/FVC ratio (72 +/- 1% versus 77 +/- 2%, p less than 0.05), higher percentage of BAL eosinophils (2.2 +/- 0.4% versus 0.6 +/- 0.1%, p less than 0.002), and greater airway responsiveness (lower PD20 [13.1 +/- 3.4 versus 41.5 +/- 13.7 cumulative breath units, p less than 0.05]) compared with asthmatics with low BAL fluid histamine (less than 100 pg/ml, n = 23).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Experimental rhinovirus 16 infection potentiates histamine release after antigen bronchoprovocation in allergic subjects.

Viral respiratory infections exacerbate asthma in many patients. We hypothesized that one mechanism by which this effect occurs may include potentiated or altered mediator release by mast cells and/or basophils to favor the development of late-phase asthmatic reaction (LAR). Therefore, we studied eight subjects with allergic rhinitis before and during an experimentally induced rhinovirus 16 (RV16) infection. We determined levels of plasma histamine and tryptase, and we observed the associated patterns of airway obstruction that developed following inhaled antigen challenge. Bronchial responsiveness to histamine, methacholine, and antigen were all significantly increased during the RV16 illness. Further, the incidence of LAR was significantly higher (five of eight) during the infection than before (one of eight; p = 0.014). In addition, in those patients whose pattern of response following antigen challenge converted from an immediate response only before infection to a dual response (immediate + late phase) during infection, plasma histamine concentrations after challenge were significantly greater than in those whose pattern of response did not change. We conclude that one mechanism by which RV16 infection increases the likelihood of LAR could include enhanced mediator release from pulmonary mast cells or from circulating or recruited basophils.

Adult↗
PubMed1991

Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge. Characterization of eosinophil and mast cell mediators.

Segmental antigen bronchoprovocation was used to define the nature of the inflammatory process in allergic airway disease. Bronchoalveolar lavage fluid obtained from allergic rhinitis patients 12 min after segmental antigen instillation (immediate response) revealed a significant increase in histamine and tryptase, but no cellular response. Repeat segmental lavage 48 h later (late response) showed marked and significant increases in both low and normal density eosinophils as well as striking elevations of eosinophil granular protein levels (major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and eosinophil peroxidase). Leukotriene C4, but not tryptase, concentrations were also consistently elevated in late lavage samples. Further, the late lavage samples showed a significant increase in interleukin-5 concentrations that correlated with the presence of eosinophils and eosinophil granular proteins. Neither eosinophils nor soluble mediators of eosinophils increased when normal subjects were similarly challenged with antigen. These data suggest that eosinophils are attracted to the airway during the late-phase allergic reaction and that IL-5 may produce changes in airway eosinophil density and promote the release of granular proteins to cause airway injury.

Adult↗
PubMed1991

In vitro incubation with influenza virus primes human polymorphonuclear leukocyte generation of superoxide.

Viral respiratory illnesses exacerbate asthma, increase airway responsiveness, and enhance the frequency of late asthmatic reactions. A number of mechanisms have been identified to explain how respiratory viral illnesses provoke wheezing, including enhanced inflammatory activity of leukocytes. To further understand how respiratory virus-caused illnesses promote leukocyte-dependent airway injury, the following study evaluated the effect of an in vitro incubation of influenza A virus on human polymorphonuclear leukocyte (PMN) generation of superoxide (O2-). PMNs were isolated from anticoagulated human blood following density gradient centrifugation; purified PMNs were then incubated (37 degrees C x 30 min) with influenza virus (PMN:virus ratio of 5:1 [egg-infective dose 50%] and 10:1) in the presence of 10% autologous serum. After incubation, the viable PMNs (greater than 95% exclusion of trypan blue) were activated, by the chemotactic peptide formyl-methionine-leucine-phenylalanine (fMLP), calcium ionophore A23187, or phorbol myristate acetate (PMA), and O2- generation was then measured. Generation of O2- to fMLP and A23187 was significantly enhanced from PMNs that had been incubated with influenza virus. Although influenza virus itself did not generate O2-, it caused a transient increase in intracellular calcium ([Ca2+]i), when measured with Indo-1-loaded cells. These results suggest that influenza virus primes PMNs to generate increased amounts of O2- and that the priming effect is associated with a transient increase in [Ca2+]. Consequently, we postulate that influenza virus priming produces PMNs of enhanced inflammatory potential to cause greater airway injury, obstruction, and responsiveness during a viral respiratory infection.

Adult↗
PubMed1990

The appearance of hypodense eosinophils during interleukin-2 treatment.

Based on membrane receptors, metabolic activity, and cell density, human eosinophils (EOSs) are a heterogeneous population of leukocytes. EOS heterogeneity translates into biologic significance, since low density cells can be metabolically more active and thus more capable of causing tissue injury. Efforts to identify mechanisms that lead to the development of hypodense EOSs have found that an in vitro exposure to cytokines reduces cell density and is associated with increased cell activity. Consequently, we evaluated the effect of an in vivo administration of interleukin-2 (IL-2) on the cell counts and density of circulating EOSs in six patients who received IL-2 as cancer biologic-modifier therapy. To determine the pattern of EOS density in relationship to IL-2 treatment, granulocyte suspensions were isolated from peripheral blood and then centrifuged over multiple discontinuous density Percoll gradients. During IL-2 treatment, the percentage of circulating hypodense EOSs increased significantly (p less than 0.01) until nearly all (97.6 +/- 1.6%) EOSs were hypodense (density less than 1.095 gm/ml). Similarly, the absolute blood EOS counts significantly increased throughout treatment. On completion of IL-2 therapy, the EOS counts and density distribution returned to pretreatment values. In contrast, no increase in blood EOS counts was observed in similar patients receiving interferon (gamma or beta) therapy. Our observations support a hypothesis that IL-2, either directly or, more likely, through the generation of other factors, participates in a change in EOS density that may, in turn, establish a subpopulation of cells with altered metabolic activity.

Adult↗
PubMed1990

Respiratory infections: their role in airway responsiveness and the pathogenesis of asthma.

The effects of RVIs on airway reactivity are multiple but do not necessarily include direct changes in the intrinsic contractile properties of airway smooth muscle. Rather, respiratory viruses influence bronchial smooth muscle function through a variety of other mechanisms: production of virus-specific IgE antibodies, epithelial injury, polymorphonuclear-dependent inflammation, and enhanced mediator release. Thus, a common pathway to airway hyper-reactivity during respiratory viral illnesses is an overall enhancement of factors that cause or lead to inflammation. When the airways become the target of enhanced inflammation, bronchial reactivity and obstruction are accentuated. Although many questions remain to be answered, future studies to evaluate the biology of respiratory virus effects on mechanisms of allergic sensitization and airway responsiveness promise to provide a greater understanding of the pathogenesis of asthma.

Asthma↗