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2.
PLoS One ; 4(4): e5134, 2009.
Article in English | MEDLINE | ID: mdl-19347046

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: To begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value

Subject(s)
Idiopathic Pulmonary Fibrosis/genetics , Base Sequence , Disease Progression , Gene Expression Profiling , Genetic Markers , Humans , Immunohistochemistry , Phenotype , Polymerase Chain Reaction , RNA, Messenger/genetics
3.
Int J Biochem Cell Biol ; 37(6): 1281-95, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15778091

ABSTRACT

The embryonic Wnt/beta-catenin ('canonical') pathway has been implicated in epithelial regeneration. To investigate the role of Wnt signal transduction in the airways, we characterised the expression of key pathway components in human bronchial epithelial cells (HBEC) and studied the influence of cell density on pathway activity, using sub-confluent cells in log-phase growth as a simple model of repairing epithelium. Primary HBEC and H292 bronchial epithelial cells were found to express TCF-4, TCF-3 and isoforms of LEF-1, transcription factors that are regulated by Wnt signalling. The cells also had the potential to respond to Wnt signalling through expression of several members of the Frizzled receptor family, including FZD-5 and -6. In confluent H292 cells, 20 mM lithium and 25% v/v Wnt-3a conditioned medium induced 4.5-fold (p = 0.008) and 1.4-fold (p = 0.006) increases in TOPflash activity, respectively. Under conditions of reduced cell density, TOPflash activity increased 1.8-fold (p = 0.002) in association with increased nuclear localisation of hypophosphorylated (active) beta-catenin and increased cell proliferation. This up-regulation in reporter activity occurred independently of EGF receptor activation and could not be recapitulated by use of low-calcium medium to disrupt cadherin-mediated cell-cell adhesion, but was associated with changes in FZD-6 expression. We conclude that reactivation of this embryonic pathway may play an important role in bronchial epithelial regeneration, and that modulation of Fzd-6 receptors may regulate Wnt signalling at confluence. Recognising that many chronic inflammatory disorders of the airways involve epithelial damage and repair, altered Wnt signalling might contribute to disease pathogenesis or progression.


Subject(s)
Cytoskeletal Proteins/physiology , Epithelial Cells/metabolism , Trans-Activators/physiology , Transcription Factors/biosynthesis , Transcription, Genetic/drug effects , Transcriptional Activation/drug effects , Adolescent , Adult , Bronchi/cytology , Bronchi/metabolism , Cell Adhesion/drug effects , Cell Count , Cell Line , Culture Media, Conditioned , DNA-Binding Proteins/biosynthesis , Epithelial Cells/drug effects , ErbB Receptors/physiology , Frizzled Receptors , Humans , Intercellular Signaling Peptides and Proteins/physiology , Lymphoid Enhancer-Binding Factor 1 , Receptors, G-Protein-Coupled/biosynthesis , Signal Transduction/physiology , Wnt Proteins , beta Catenin
4.
Am J Respir Crit Care Med ; 170(6): 583-93, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15172898

ABSTRACT

IgE plays an important role in allergic asthma. We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2% or more were treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced sputum and bronchial biopsies, and methacholine responsiveness. Treatment with omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa. The mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was associated with a significant reduction in tissue eosinophils; cells positive for the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B lymphocytes; and cells staining for interleukin-4, but not with improvement in airway hyperresponsiveness to methacholine. This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma. The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Immunoglobulin E/immunology , Respiratory Mucosa/immunology , Adult , Anti-Asthmatic Agents/immunology , Antibodies, Anti-Idiotypic , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized , Asthma/immunology , Bronchi/drug effects , Bronchi/immunology , Double-Blind Method , Eosinophilia/immunology , Female , Humans , Inflammation/immunology , Male , Middle Aged , Omalizumab , Respiratory Mucosa/drug effects , Sputum/immunology , Treatment Outcome
5.
J Allergy Clin Immunol ; 110(6): 906-14, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12464958

ABSTRACT

BACKGROUND: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma has been shown to be dependent on CD28/B7 costimulation. OBJECTIVE: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma. METHODS: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique. The contribution of IL-16 to the activity was evaluated through use of a neutralizing monoclonal antibody; the contribution of CD28/B7 costimulation to allergen-induced release of TLCA was determined through use of CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and CD86 (B7.2). RESULTS: Induced sputum and unstimulated explants from asthmatic subjects generated significant spontaneous TLCA (P <.05). Both mild and moderate asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus -induced release of TLCA, but only in mild asthma could sputum and allergen-stimulated explant TLCA be inhibited by anti-IL-16 (median inhibition, 39% and 59%; P <.05). In addition, allergen released significant quantities of IL-16 from mild asthmatic explants (P <.05) but not from moderate asthmatic explants. Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced release of TLCA in mild asthmatic explants by 94% (P <.05) and 62%, but TLCA release from moderate asthmatic explants was unaffected by CTLA4-Ig. CONCLUSION: These results show that TLCA release in moderate asthmatic airways, in contrast to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not involve IL-16.


Subject(s)
Asthma/immunology , B7-1 Antigen/physiology , Bronchi/immunology , CD28 Antigens/physiology , Chemotaxis, Leukocyte/immunology , Immunoconjugates , Interleukin-16/physiology , T-Lymphocytes/immunology , Abatacept , Adult , Antigens, CD/physiology , Antigens, Differentiation/physiology , B7-2 Antigen , CTLA-4 Antigen , Female , Humans , Male , Membrane Glycoproteins/physiology , Middle Aged , Sputum/immunology
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