Epithelial repair is inhibited by an alpha(1,6)-fucose binding lectin.

The effective repair of damage to the airway epithelium is essential to maintain the ability to exclude airborne particulates and protect against potential pathogens. Carbohydrates on the cell surface have an important role in cell-cell and cell substrate interactions. Using a model of repair with airway epithelial-derived cells of the 16HBE 14o(-) cell line, we have examined the effect of the Aleuria aurantia lectin (AAL), which binds very selectively to alpha(1,6)-linked fucose residues.

Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments.

Chronic fatigue syndrome (CFS) is an illness characterised by disabling fatigue of at least 6 months duration, which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed to deal with the current areas for development in CFS research--namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of patients with CFS, and from those studies that have been confirmed using polymerase chain reaction (PCR), clearly, the most predominant functional theme is that of immunity and defence.

The mechanisms, diagnosis, and management of severe asthma in adults.

There has been a recent increase in the prevalence of asthma worldwide; however, the 5-10% of patients with severe disease account for a substantial proportion of the health costs. Although most asthma cases can be satisfactorily managed with a combination of anti-inflammatory drugs and bronchodilators, patients who remain symptomatic despite maximum combination treatment represent a heterogeneous group consisting of those who are under-treated or non-adherent with their prescribed medication. After excluding under-treatment and poor compliance, corticosteroid refractory asthma can be identified as a subphenotype characterised by a heightened neutrophilic airway inflammatory response in the presence or absence of eosinophils, with evidence of increased tissue injury and remodelling.

Role of deficient type III interferon-lambda production in asthma exacerbations.

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity.

Human bronchial fibroblasts express the 5-lipoxygenase pathway.

Background: Fibroblasts are implicated in sub-epithelial fibrosis in remodeled asthmatic airways and contribute to airway inflammation by releasing cytokines and other mediators. Fibroblast activity is influenced by members of the leukotriene family of bronchoconstrictor and inflammatory mediators, but it is not known whether human bronchial fibroblasts can synthesize leukotrienes.

Methods: The expression of leukotriene biosynthetic enzymes and receptors was investigated in primary fibroblasts from the bronchi of normal and asthmatic adult subjects using RT-PCR, Western blotting, immunocytochemistry and flow cytometry.

Susceptibility genes in severe asthma.

Asthma is a common complex disease with a very wide spectrum of severity. Although part of this may be due to differing environmental interactions and inadequate treatment, there is increasing evidence that in addition to susceptibility genes for asthma onset, there are also important genetic influences over the disease severity, response to treatment, and natural history. In this review, we bring together recent literature in the field of genetic influences over disease severity and discuss some of the clinical implications in terms of drug discovery and personalized medicine.

The genetics of asthma: ADAM33 as an example of a susceptibility gene.

The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling.

Adenosine receptors as promising therapeutic targets for drug development in chronic airway inflammation.

A growing body of evidence has emerged in support of a pro-inflammatory role for adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and COPD. The demonstration that adenosine enhances mast cell allergen-dependent activation, the notion that elevated levels of adenosine are present in chronically inflamed airways, and the results from exposure studies of nebulised adenosine showing dose-dependent bronchoconstriction in subjects with asthma and COPD, emphasise the importance of adenosine in the initiation, persistence and progression in these common inflammatory disorders of the airways. Adenosine exerts its manifold biological activities by interacting with at least four adenosine receptor subtypes.

The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma.

Background: The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma.

Methods: Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1.

The sound of death rattle II: how do relatives interpret the sound?

Background: In an earlier study, we found that some bereaved relatives (five out of 12 interviewed) found it distressing to hear the sound of death rattle, but the remainder did not. In this paper, we report a second study in which we explored how a different group of relatives interpreted the sound of death rattle when they heard it.

Method: We conducted face-to-face semi-structured interviews with 25 bereaved relatives using the principles of grounded theory.

The sound of death rattle I: are relatives distressed by hearing this sound?

Background: Death rattle is the noisy, rattling breathing that occurs in many dying patients. Health professionals intervene because the sound is said to distress attendant relatives. We found no formal study to confirm or refute relatives' distress, so we decided to ask the relatives.

IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets.

IL-4 is a key cytokine associated with allergy and asthma. Induction of cell signaling by IL-4 involves interaction with its cognate receptors, a complex of IL-4Ralpha with either the common gamma-chain or the IL-13R chain alpha1 (IL-13Ralpha1). We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4Ralpha) with high affinity and specificity.

The role of the mast cell in the pathophysiology of asthma.

There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function.

Adenosine signalling in airways.

Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD.

Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities.

Although asthma is defined in terms of reversibility of airflow obstruction, as the disease becomes more severe and chronic, it adopts different characteristics, including a degree of fixed airflow obstruction and corticosteroid refractoriness. Underlying these phenotypes is evidence of airway wall remodeling, which should be distinguished from the increase in smooth muscle linked to airways hyperresponsiveness. Aberrant epithelial-mesenchymal communication leads to a chronic wound scenario, which is characterized by activation of the epithelial-mesenchymal trophic unit, epithelial damage, the laying down of new matrix, and greater involvement of neutrophils in the inflammatory response.

The role of Toll-like receptors and related receptors of the innate immune system in asthma.

Purpose Of Review: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma.

Enhanced upregulation of smooth muscle related transcripts by TGF beta2 in asthmatic (myo) fibroblasts.

Background: Transforming growth factor beta (TGF beta) upregulates a number of smooth muscle specific genes in (myo)fibroblasts. As asthma is characterised by an increase in airway smooth muscle, we postulated that TGFbeta(2) favours differentiation of asthmatic (myo)fibroblasts towards a smooth muscle phenotype.

Methods: Primary fibroblasts were grown from bronchial biopsy specimens from normal (n = 6) and asthmatic (n = 7) donors and treated with TGF beta2 to induce myofibroblast differentiation.

The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma.

Asthma is increasing in prevalence in the developing world, affecting approximately 10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time. Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity.

Association of asthma with a functional promoter polymorphism in the IL16 gene.

Background: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described.

Objective: We sought to examine the functional significance of this promoter SNP and its relationship to asthma.

ADAM33: a newly identified gene in the pathogenesis of asthma.

There is much to find out about this fascinating and complex molecule in relation to the development and progression of asthma. Added to it are three further new asthma/allergy genes identified by positional cloning: PDH Finger Protein II (PHF11) on chromosome 13q14, which encodes NY-REN-34 a protein first described in patients with renal cell carcinoma [67]; Dipeptidyl diptidase 10 (DDP10) on chromosome 2q14 [68]; and G protein-coupled receptor for asthma susceptibility (GPRA) on chromosome 7p [69]. For each of these genes, as is the case for ADAM33, determining their normal function(s) and how these become disordered in asthma is the future challenge.

Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma.

Background: Very late antigen (VLA-4) antagonists have been proposed as potential therapies for diseases in which cell recruitment and accumulation are causative. Asthma, which is characterized by airway inflammation involving the accumulation of eosinophils and mononuclear cells, is one such disease.

Objective: We sought to assess the effect of IVL745, a VLA-4 antagonist, on the early and late asthmatic response (LAR) and on markers of airway inflammation after allergen inhalation.

Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma.

Background: Tumour necrosis factor alpha (TNFalpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFalpha is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFalpha.

Environmental risk factors and allergic bronchial asthma.

The prevalence of allergic respiratory diseases such as bronchial asthma has increased in recent years, especially in industrialized countries. A change in the genetic predisposition is an unlikely cause of the increase in allergic diseases because genetic changes in a population require several generations. Consequently, this increase may be explained by changes in environmental factors, including indoor and outdoor air pollution.