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Abstract Background Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness. Methods In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (WT) and area (WA) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels. Results Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in WA (67.5 ± 5.4 vs 66.4 ± 5.4) and WT/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of √wall area to Pi was negatively correlated with FEV1% predicted (p < 0.05). Conclusions Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.

Therapeutic advances using targeted biologicals and small‐molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment‐resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg‐based approaches, in severe IgE‐mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment‐resistant forms of these immune‐driven disorders. [ABSTRACT FROM AUTHOR]

Background: Airway wall remodelling and inflammation are features of chronic asthma. Transforming growth factor beta (TGF-beta) has been implicated in these processes.Aim: To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF-beta isoforms and the Smad signalling pathways are involved.Methods: Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3-4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy.Results: Forced expiratory volume in 1 s (FEV(1)) fell after allergen challenge (mean (SE) -28.1 (0.9)% at 30 min with a late response at 7 hours (-23.0 (1.2)%). Allergen challenge caused an increase in neutrophils and eosinophils in the bronchial mucosa compared with saline. Sub-basement membrane (SBM) thickness did not change after allergen, but tenascin deposition in SBM was increased. Intranuclear (activated) Smad 2/3 and Smad 4 detected by immunohistochemistry were increased after allergen challenge in epithelial and subepithelial cells of bronchial biopsies. No inhibitory Smad (Smad 7) protein was detected. TGF-beta isoforms 1, 2 and 3 were expressed predominantly in bronchial epithelium after saline and allergen challenges, but only TGF-beta(2) expression was increased after allergen. Double immunostaining showed an increase in TGF-beta(2) positive eosinophils and neutrophils but not in TGF-beta(1) positive eosinophils and neutrophils after allergen challenge.Conclusions: TGF-beta(2) may contribute to the remodelling changes in allergic asthma following single allergen exposure. [ABSTRACT FROM AUTHOR]

Inflammatory gene expression in airway smooth muscle may be influenced by its inflammatory milieu. We analysed the gene expression profile of airway smooth muscle cells cultured from human airways exposed to a pro-inflammatory cytokine, interleukin-1β, a T helper-2 cytokine, interleukin-13, and to a growth factor, transforming growth factor (TGF)β1 (10 ng/ml each) after 4 and 24 h using the Affymetrix GeneChip 95A array which detects ∼12,500 genes and expression sequence tags (ESTs). Airway smooth muscle cells were responsive to each cytokine with distinctive patterns of gene expression for cytokines, chemokines, adhesion and signalling proteins, and transcription factors. Interleukin-1β induced the highest number of genes such as cytokines/chemokines including interleukin-8, growth-related oncogene (GRO)-α, -β and -γ, epithelial neutrophil activating protein (ENA)-78, monocyte chemotactic protein (MCP)-1, -2 and -3 and eotaxin. Using quantitative real-time reverse transcription-polymerase chain reaction, the expression of GRO-α, -β and -γ, interleukin-8 and eotaxin by interleukin-1β was confirmed, with good correlation with microarray data. Transforming growth factor (TGF)β1 induced other growth factors such as connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), insulin growth factor (IGF) and many structural and extracellular matrix proteins. Interleukin-13 was the weakest inducer, with stimulation of eotaxin and genes of unknown function. While many genes were co-regulated at 4 and 24 h, there were also differences in expression patterns. Interleukin-1β induces a predominantly pro-inflammatory profile while TGFβ1 can be linked to proliferative and matrix changes. The rich profile of mediators, growth factors and signalling molecules released from airway smooth muscle depends on the inflammatory milieu. [Copyright &y& Elsevier]