Tumour necrosis factor-α regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-κB and AP-1.

Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses.

Sublingual immunotherapy for treating allergic conjunctivitis.

Background: Allergic ocular symptoms, although frequently trivialised, are common and represent an important comorbidity of allergic rhinitis. Sublingual Immunotherapy (SLIT) is an effective and well-tolerated treatment for allergic rhinitis, but its effects on symptoms of ocular allergy have not been well established.

Objectives: To evaluate the efficacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirements and conjunctival immediate allergen sensitivity.

Allergen injection immunotherapy for seasonal allergic rhinitis.

Background: Allergic rhinitis is the most common of the allergic diseases. Despite improved understanding of the pathophysiology of allergic rhinitis and advances in its pharmacological treatment, its prevalence has increased worldwide. For patients whose symptoms remain uncontrolled despite medical treatment, allergen injection immunotherapy is advised.

Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma.

Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound.

Early allergen exposure, skin prick responses, and atopic wheeze at age 5 in English children: a cohort study.

Background: For many years it has been assumed that the risk of childhood respiratory allergies is related to allergen exposures in early life. There are, however, few prospective data in support. We aimed to examine this relationship in a representative cohort of children born in Ashford, Kent (UK).

Protective ventilation of patients with acute respiratory distress syndrome.

The majority of patients with acute respiratory distress syndrome (ARDS) require mechanical ventilation. This support provides time for the lungs to heal, but the adverse effects of mechanical ventilation significantly influence patient outcome. Traditionally, these were ascribed to mechanical effects, such as haemodynamic compromise from decreased venous return or gross air leaks induced by large transpulmonary pressures.

Early prescriptions of antibiotics and the risk of allergic disease in adults: a cohort study.

Background: It is frequently asserted that antibiotic prescriptions in childhood are associated with the development of allergic disease, especially asthma. A study was undertaken to establish the direction of this relationship.

Methods: A retrospective cohort study of 746 adults was performed in three general practices.

Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy.

Background: Among atopic individuals, levels of allergen-specific IgG antibodies have been inversely associated with the degree of allergen sensitization. Additionally, allergen-specific IgG antibodies are markedly increased by allergen injection immunotherapy. These observations have led to proposals that allergen-specific IgG antibodies might have protective properties in atopic individuals.

Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD.

Background: Exacerbations are an important feature of chronic obstructive pulmonary disease (COPD), accounting for a large proportion of health care costs. They are associated with increased airway inflammation and oxidative stress.

Methods: Concentrations of leukotriene B4 (LTB4), a marker of inflammation, and 8-isoprostane, a marker of oxidative stress, were measured in the exhaled breath condensate of 21 patients (11 M) with COPD during an exacerbation and 2 weeks after treatment with antibiotics.

Slower rise of exhaled breath temperature in chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD) there is decreased vascularity of the bronchi and inflammation of the airways that may have opposite effects on the regulation of heat loss. Exhaled air temperature increase (delta(e) T) was measured in 23 patients with moderate COPD (18 male, mean age +/- SEM 70 +/- 1 yrs; forced expiratory volume in one second (FEV1) 45 +/- 3%, FEV1/forced vital capacity 54 +/- 4%) and 16 normal volunteers (64 +/- 4 yr) and compared to exhaled nitric oxide (eNO) and inflammatory cells in induced sputum as a marker of airway inflammation. Delta(e) T was measured during a flow- and pressure-controlled single exhalation with a fast-response thermometer.

Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis.

We have examined the role of caspase-mediated cleavage of the Ste20-like kinases, mammalian sterile 20-like 1 and 2 (Mst1/Mst2), in the mechanism of human eosinophil and neutrophil apoptosis. Initial measurements of kinase activity, using myelin basic protein (MBP) as a substrate in "in-gel" renaturation assays, showed that constitutive eosinophil and neutrophil apoptosis were associated temporally with the activation of a 36-kd MBP kinase (p36 MBPK) and a 34-kd MBP kinase (p34 MBPK), respectively. A constitutively active 63-kd MBP kinase (p63 MBPK) was also detected in freshly prepared eosinophils but not neutrophils, whose activity was transiently augmented during spontaneous apoptosis.

p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma.

Background: Although glucocorticoids are the most effective treatment for chronic inflammatory diseases, such as asthma, some patients show a poor response. IL-2 combined with IL-4 can alter glucocorticoid receptor (GR) ligand-binding affinity and modulate glucocorticoid function.

Objective: We sought to confirm the altered ligand-binding affinity in a distinct group of steroid-dependent asthmatic subjects and examine the mechanism by which IL-2 and IL-4 modify the ligand-binding affinity of the GR.

The nasal epithelium as a factory for systemic protein delivery.

We have previously shown that recombinant Sendai virus (SeV) produces efficient in vivo airway epithelial gene transfer. The ability to produce therapeutic levels of circulating proteins following noninvasive gene transfer would have widespread clinical application. Here, we compared nose, lung, and skeletal muscle for the ability to produce circulating levels of the secreted mouse antiinflammatory cytokine interleukin-10 (IL10) following SeV-mediated gene transfer.

Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics.

IgE is important in both early and late allergic responses. Increases in the numbers of RNA transcripts coding for IgE have been observed in the bronchial mucosa of asthmatics and in the nasal mucosa of hay fever patients both during natural allergen exposure and after nasal allergen challenge, suggesting that IgE may be synthesized locally in the mucosa. In this study we have examined bronchoalveolar lavage (BAL) taken before and 24 h after bronchoscopic segmental allergen challenge from 18 atopic asthmatic patients, looking for evidence of increases in IgE protein.

Eosinophils, eosinophilic cytokines (interleukin-5), and antieosinophilic therapy in asthma.

Eosinophils are believed to be key effector cells in producing the bronchial mucosal inflammation characteristic of allergic asthma. Given the perceived importance of eosinophils in allergic inflammation, they have been logical therapeutic targets. As knowledge of eosinophil biology increases, eosinophils are targeted with specific therapies blocking their maturation, activation, and chemotaxis.

Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium.

Background: Symptoms of allergic rhinitis are accompanied by infiltration of the nasal mucosa with inflammatory cells, predominantly eosinophils and metachromatic cells (basophils and mast cells). Specific immunotherapy (IT) reduces mucosal eosinophilia and numbers of metachromatic cells in the epithelium. A specific marker distinguishing basophils from mast cells was recently developed.

Pharmacological comparison of LTB(4)-induced NADPH oxidase activation in adherent and non-adherent guinea-pig eosinophils.

1. Leukotriene B(4) (LTB(4)) stimulation of guinea-pig peritoneal eosinophils, induced a biphasic activation of the NADPH oxidase composed of a rapid (<3 min) phase mediated by non-adherent cells and a sustained (3 - 120 min) phase mediated by CD11b/CD18 adherent eosinophils. Studies were undertaken to compare the intracellular mechanism that mediate these responses.

Proliferation and release of IL-5 and IFN-gamma by peripheral blood mononuclear cells from cat-allergic asthmatics and rhinitics, non-cat-allergic asthmatics, and normal controls to peptides derived from Fel d 1 chain 1.

Background: In general, T cells from normal, nonatopic individuals respond to aeroallergens with synthesis and release of IFN-gamma. In contrast, release of T(H)2-type cytokines by activated lymphocytes is a feature of allergic rhinitis and atopic asthma.

Objective: The purpose of this study was to determine differences in T-cell recognition of epitopes within allergenic sequences, in terms of proliferation and cytokine production, in subjects with atopic asthma compared with subjects with allergic rhinitis and normal controls.

Increased nitrotyrosine in exhaled breath condensate in cystic fibrosis.

Exhaled nitric oxide (ENO), a marker of inflammation in airway diseases is decreased in cystic fibrosis (CF) patients, perhaps because nitric oxide (NO) is metabolized to oxidative end-products. A stable product, 3-nitrotyrosine, may indicate local formation of reactive nitrogen species. Whether NO metabolites in exhaled breath condensate may be increased in CF patients was investigated.

Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial.

Background: Controlled trials suggest that leukotriene receptor antagonists can improve lung function and reduce requirement for oral or inhaled corticosteroids in patients with asthma. We aimed to assess whether montelukast, a leukotriene receptor antagonist, can improve symptoms or lung function in patients with chronic asthma with symptoms already taking corticosteroids.

Methods: We did a double-blind, placebo-controlled, crossover, randomised add-on study in which 100 patients with asthma and symptoms despite treatment with inhaled corticosteroids and additional therapy were given 10 mg montelukast sodium for 14 days in an outpatient clinic setting.

Analysis of allergens in rat fur and saliva.

Background: The fur is an important source of allergens in many mammal species, but this source has not been extensively studied in rats. Rat room dust contains high-molecular-weight allergens that have been found to cross-react with fur and its presumed salivary contaminants. The role of rat fur and saliva as a source of respiratory allergens merits further investigation.

Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season.

Background: Tissue eosinophilia and infiltration by T(H)2-type T cells are characteristic features of allergic rhinitis both after allergen challenge and during natural allergen exposure. Specific immunotherapy inhibits allergen-induced nasal eosinophilia.

Objectives: We sought to assess, in the context of a randomized trial, the relationships between symptomatic improvement after immunotherapy and eosinophil numbers and IL-5 expression in the nasal mucosa during the pollen season.

p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex.

Glucocorticoids acting through their specific receptor can either enhance or repress gene transcription. Dexamethasone represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associated histone acetyltransferase (HAT) activity and by recruiting histone deacetylase 2 (HDAC2) to the p65-HAT complex. Here we show that mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene expression but represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor release by 50% maximally.