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Summary: Background: Epidemics of asthma and overweight have been linked recently. They might be associated with systemic inflammation. In asthma hyperresponsiveness to adenosine (AMP) is more closely related to inflammation than to methacholine (MCh). The aim of the study was to determine responsiveness to AMP and MCh in overweight compared with normal weight asthmatics. Methods: Thirty women were enrolled (19 overweight) with mild controlled asthma according to GINA. A Body Mass Index (BMI) less than 25kg/m2 was considered as normal and a BMI above 25kg/m2 as overweight. We assessed the recent control of asthma (ACQ), pulmonary function tests, bronchial responsiveness to MCh and AMP (PC20 and O''Connor two-point dose–response slope), perception of symptoms (Borg scale), and blood inflammatory markers (leptin and hs-CRP by ELISA). Results: Overweight had a significant lower dose-response slope of the MCh challenge (p =0.009) as compared to normal weight patients, whereas no significant difference was observed for AMP challenge (p =0.27). Overweight patients had higher intercepts of the Borg scale measured before the MCh and AMP challenge tests (p =0.01 and p =0.03). Plasma leptin (p =0.001) and hs-CRP (p =0.05) concentrations were higher in overweight than normal weight patients. There was no correlation between challenges and inflammatory markers. Conclusions: Overweight asthmatic women have more pronounced systemic inflammation, but are less responsive to MCh. AMP responsiveness appeared to be comparable between both groups. Our findings suggest that overweight asthmatic women do not feature increased airway inflammation, but do represent a distinct phenotype as compared to normal weight patients. [Copyright &y& Elsevier]

Background: Severe asthma is characterized by neutrophilic inflammation and high levels of interleukin (IL)-8. Airway epithelial cells play a pivotal role in the pathogenesis and chronicity of asthma. The objective of this work was to determine whether CXC receptors were involved in human small airway epithelial cell (SAEC) activity by incubating them with IL-8; the investigation also included a proteomic approach. Methods: IL-6 and intercellular adhesion molecule-1 (ICAM-1) were assessed by ELISA and flow cytometry, respectively. CXCR-1 and CXCR-2 receptor mRNA and protein expressions were analyzed by RT-PCR, immunocytochemistry and flow cytometry. Cells were incubated with different concentrations (0–100 ng/ml) of IL-8. The involvement of both receptors was assessed using specific antibodies. Results: Only the CXCR-1 receptor was expressed in SAECs. IL-8 (50 ng/ml, 12 h) induced the release of IL-6 and had no effect on ICAM-1. Supernatants analyzed by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) showed very weak differences in peptide profiles. Interestingly, 4,820-m/z peptide release was detected in the presence of IL-8 and abolished by CXCR-1 antibody. Discussion: The present study illustrated the fact that IL-8 mediated by CXCR-1 increased IL-6. We also highlight the usefulness of SELDI ProteinChip technology to confirm the potential variation of peptide profile. Moreover, we were able to detect the 4,820-m/z peptide secreted in vitro by human airway epithelial cells induced by IL-8 via CXCR-1 receptor. Determination of the protein secretion profile in response to inflammatory stimuli could be an important therapeutic strategy in severe asthma. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Structural changes to the airways are features of severe asthma. The bronchial epithelium facilitates this remodeling process. Learning about the changes that develop in the airway epithelium could improve our understanding of asthma pathogenesis and lead to new therapeutic approaches. Objective: We sought to determine the feasibility and relevance of air-liquid interface cultures of bronchial epithelium derived from endobronchial biopsy specimens of patients with different severities of asthma for studying the airway epithelium. Methods: Human bronchial epithelial cells derived from endobronchial biopsy specimens of patients with mild and severe asthma were maintained in culture for 21 days in an air-liquid interface to reproduce a fully differentiated airway epithelium. Initially, features of remodeling that included epithelial and subepithelial layers, as well as mucus production, were assessed in paraffin-embedded endobronchial biopsy specimens to evaluate morphologic characteristics of asthmatic patients’ epithelia. Ex vivo differentiated epithelia were then analyzed for morphology and function based on ultrastructural analysis, IL-8 release, lipoxin A4 generation, mucin production, and lipoxygenase gene expression. Results: Morphologic and inflammatory imbalances initially observed in endobronchial biopsy specimens obtained from patients with severe or mild asthma persisted in the air-liquid interface reconstituted epithelium throughout the differentiation process to 21 days. Epithelium from patients with severe asthma produced greater levels of mucin, released more IL-8, and produced lower levels of lipoxin A4 than that from patients with mild asthma. Expression of 15-lipoxygenase 2 was increased in epithelium from patients with severe asthma, whereas expression levels of MUC5AC, MUC5B, 5-lipoxygenase, and 15-lipoxygeanse 1 were similar to those of patients with mild asthma. Conclusion: Ex vivo cultures of fully differentiated bronchial epithelium from endobronchial biopsy specimens maintain inherent phenotypic differences specifically related to the severity of asthma. [Copyright &y& Elsevier]