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Background: The prevalence and severity of asthma is believed to increase with increasing socioeconomic deprivation. The relationship between asthma diagnosis, symptoms, diagnostic accuracy, and socioeconomic deprivation as determined by Townsend scores was determined in Sheffield schoolchildren. Methods: All 6021 schoolchildren aged 8-9 years in one school year in Sheffield were given a parent respondent survey based on International Survey of Asthma and Allergies in Childhood (ISAAC) questions. Results: 5011/6021 (83.2%) questionnaires were returned. Postcode data were available in 4131 replies (82.4%) and were used to assign a composite deprivation score (Townsend score). Scores were divided into five quintiles, with group 1 being least and group 5 being most deprived. A positive trend was observed from group 1 to group 5 for the prevalence of wheeze in the previous 12 months, wheeze attacks &ges;4/year, nocturnal wheeze and cough (all p<0.001), cough and/or wheeze "most times" with exertion (p<0.03), current asthma (p<0.001), and significant asthma symptoms (p<0.001). No significant trend was observed for lifetime wheeze or attacks of speech limiting wheeze. There were no significant trends in the prevalence of current asthmatic children without significant symptoms (over-diagnosis) or children with significant asthma symptoms but no current asthma diagnosis (underdiagnosis) across the social groups. There was a significant negative trend in the ratio of asthma medication to asthma diagnosis from least to most deprived groups (p<0.001). Conclusions: Asthma morbidity and severity increase according to the level of socioeconomic deprivation. This may be due to differences in environment, asthma management, and/or symptom reporting. Diagnostic accuracy does not vary significantly across deprivation groups but children living in areas of least deprivation and taking asthma medication are less likely to be labelled as having asthma, suggesting... [ABSTRACT FROM AUTHOR]

Viruses, such as Rhinovirus, are a major cause of asthma exacerbations. Pellino1 was identified as an interleukin 1 receptor associated kinase binding partner and has shown to act as an E3-ubiquitin ligase that is involved in Lysine-63 polyubiquitination of interleukin 1 receptor associated kinase 1/4 and RIP1, which are key mediators of the Toll-like receptor and interleukin 1 receptor (IL-1R) signalling pathways. As such, these pathways are implicated in responses to both bacterial and viral infections. However, the functional importance of Pellino proteins in regulating immune responses and their role in airway inflammatory diseases is yet to be elucidated. We hypothesised that Pellino1 would play a critical role in regulating the inflammatory response in the lung airway epithelium. Pellino1 was knocked down in the human bronchial airway epithelial cell line BEAS2B and primary human bronchial epithelial cells (PBECs) using targeted siRNA. Knockdown of Pellino1 at the transcriptional level was measured using qPCR. Pellino1 knockdown cells were stimulated with Toll-like receptor/IL-1R agonists or the natural pathogen rhinovirus 1B (RV1B) and cytokine release was measured using ELISA. Signalling pathways were explored by western blotting. Pellino1 was expressed in BEAS2B and primary bronchial epithelial cells. Pellino1 mRNA transcript level was knocked down by 78% in BEAS2B and 94% in PBECs. Pellino1 knockdown led to reduced IL-8 generation in response to IL-1β and a viral mimic Poly (I:C) stimulation in BEAS2B, however RANTES production was unchanged. In contrast to the BEAS2B, the primary bronchial epithelial cells exhibited preserved IL-1 signalling. However, these cells also showed a reduction in IL-8 production in response to both Poly (I:C) stimulation and RV1B infection. Pellino1 knockdown had no effect on the interferon-stimulated gene RANTES production. Pellino1 knockdown leads to reduced IL-8 production in response to a viral mimic Poly (I:C) in lung airway epithelial cells and RV1B in PBECs. These data indicate that Pellino1 regulates proinflammatory responses in airway epithelium and may be a feasible target to downregulate neutrophillic airway inflammation while retaining antiviral immunity, which would be highly beneficial in the treatment of chronic airway inflammatory disorders such as asthma and COPD. These studies were supported by an MRC/Asthma UK PhD studentship. [ABSTRACT FROM AUTHOR]

Introduction The concept of driving cellular apoptosis as a potential therapy for diseases characterised by inappropriate cellular persistence or proliferation is of widespread interest. We previously showed a death receptor ligand, TRAIL, accelerates neutrophil apoptosis without associated cell activation (J Immunol 170:1027-33) and other work revealed TRAIL-induced apoptosis of human lung fibroblasts. The aims of this project were to study the role of TRAIL in a bleomycin lung injury model in wild-type and TRAIL-/- mice and in patients with idiopathic pulmonary fibrosis (IPF). Methods Mice received intratracheal bleomycin or saline control. Bronchoalveolar lavage (BAL) at 3, 7, 16 and 23 days was analysed by cytospin morphology and haemocytometer count for % neutrophils, % neutrophil apoptosis, total number of neutrophils and total number of apoptotic cells. Flow cytometry was also used to analyse apoptosis. Collagen deposition in whole lung samples was analysed using a hydroxyproline assay. TRAIL expression and TUNEL positive events were also analysed. Serum and lung tissue from IPF patients/controls were examined for TRAIL expression and concentration. Lung function and survival data were retrieved from patient charts. Results BAL analysis revealed statistically significant differences between TRAIL-/- and wild-type mice, with TRAIL-/- mice showing increased neutrophil numbers and reduced neutrophil apoptosis as absolute count or as % total cell count. Collagen deposition was statistically greater in TRAIL-/- mice at 16 days. At day 23, TRAIL-/- mice had decreased TUNEL positive events compared to wild-type mice. Histological analysis of murine lung sections revealed specific TRAIL expression in bronchus associated lymphoid tissue and alveolar macrophages. IPF patient lung section analysis revealed an absence of TRAIL expression compared to controls. IPF patients had significantly lower serum levels of TRAIL than controls which inversely correlated with TLCO (% predicted) and positively correlated with survival from diagnosis. Conclusions We demonstrated that the neutrophilic inflammatory response to bleomycin is increased in TRAIL-/- compared with wild-type mice and that this finding is associated with increased collagen deposition. We also demonstrated reduced pulmonary and systemic expression of TRAIL in IPF, which correlates with worse pulmonary function and clinical outcome. This data suggests TRAIL may have biomarker potential and therapeutic benefit in pulmonary fibrosis. [ABSTRACT FROM AUTHOR]