Showing papers by "William W. Busse published in 1995"

Asthma and Rhinitis

Abstract: Part 1: Disease Classification Part 2: Epidemiology Part 3: Normal Anatomy, Development and Physiology Part 4: Pathology Part 5: Mast Cells And Basophils Part 6: Eosinophils Part 7: Neutrophils Part 8: Lymphocytes Part 9: Macrophages And Monocytes Part 10: Platelets Part 11: Fibroblasts Part 12: Epithilial Cells Part 13: Mediators Of Inflammation Part 14: Role Of Allergans In Airways Disease Part 15: Physiology Of The Airways Part 16: Smooth Muscle Response Part 17: Exercise Induced Asthma Part 18: Viral Mechanisms In Asthma And Related Disease Part 19: Clinical And Therapeutic Implications

Fluticasone Propionate Reduces Oral Prednisone Use while It Improves Asthma Control and Quality of Life

Abstract: 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.

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

Abstract: 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.

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

Abstract: 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.

Childhood- versus Adult-Onset Asthma

Abstract: Although the overall features of asthma are similar in children and adults, numerous distinctions exist. Furthermore, it is possible that for many patients with asthma, the onset of their disease be­ gins in childhood. However, efforts to study asthma have largely been restricted to adult patients. Thus, it is highly likely that key insights into asthma pathogenesis are being missed, because the onset of the disease has been well established by adulthood, and mechanisms of injury and repair are then difficult to dissect. The National Heart, Lung, and Blood Institute workshop on childhood- versus adult-onset asthma was convened to discuss unique features of childhood asthma and identify areas for study, especially areas that might help establish the important features of childhood asthma. Summarized below are the workshop presen­ tations and recommendations for future areas of investigation. Outcome Analysis of Wheezing in Children and Adults Risk factors shown to be important in reducing maximally attained lung function include wheeze or a doctor's diagnosis of asthma, active and passive cigarette smoking, airway responsiveness, and peripheral blood eosinophilia. The relative importance of these factors changes at different phases of the life cycle. For maximal lung function between the ages of 15 and 35 yr, airway respon­ siveness is the most important. Wheeze does not appear to be any more or less predictive than other respiratory symptoms of cough, sputum production, or dyspnea. Data also suggest that airway responsiveness, respiratory symptoms, and peripheral blood eosinophilia are independent risk factors for the develop­ ment of chronic obstructive disease and that the mechanism by which these factors predict this development is by reducing max­ imallung function and precipitating early decline in FE~ in chil­ dren and young adults. The development of chronic obstructive lung disease is a lifelong process involving risk factors that begin at conception.

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

Abstract: 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.

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

Abstract: 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.

The Effects of Rhinovirus Infections on Allergic Airway Responses

Abstract: 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.

Viral infections in humans.

Abstract: 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.

Corticosteroids in the Treatment of Asthma

Abstract: Asthma treatment is currently undergoing transition as recognition of the important role of anti-inflammatory therapy continues. Asthma is now recognised as a chronic inflammatory process that can be modulated by anti-inflammatory agents. The effectiveness of systemic therapy with corticosteroids has been known for decades, and aerosolised forms of corticosteroids are playing an increasingly important role in treating and preventing asthma. The early introduction of inhaled corticosteroids, along with avoidance of causal factors, may prevent or reduce progression and chronicity of this disease.