U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach. @ERSpublications Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.

Activation of peroxisome proliferator-activated receptor ␥ (PPAR␥) after balloon injury significantly inhibits VSMC proliferation and neointima formation. However, the precise mechanisms of this inhibition have not been determined. We hypothesized that activation of PPAR␥ in vascular injury could attenuate VSMC growth and matrix production during vascular lesion formation. Since connective tissue growth factor (CTGF) is a key factor regulating extracellular matrix production, abrogation of transforming growth factor ␤ (TGF-␤)-induced CTGF production by PPAR␥ activation may be one of the mechanisms through which PPAR␥ agonists inhibit neointima formation after vascular injury. In this study, we demonstrate that the PPAR␥ natural ligand (15-deoxyprostaglandin J 2 ) and a synthetic ligand (GW7845) significantly inhibit TGF-␤-induced CTGF production in a dose-dependent manner in HASMCs. In addition, suppression of CTGF mRNA expression is relieved by pretreatment with an antagonist of PPAR␥ (GW9662), suggesting that the inhibition of CTGF expression is mediated by PPAR␥. To elucidate further the molecular mechanism by which PPAR␥ inhibits CTGF expression, an ϳ2-kilobase pair CTGF promoter was cloned. We found that PPAR␥ activation inhibits TGF-␤-induced CTGF promoter activity in a dose-dependent manner, and suppression of CTGF promoter activity by PPAR␥ activation is completely rescued by overexpression of Smad3, but not by Smad4. Furthermore, PPAR␥ physically interacts with Smad3 but not Smad4 in vitro in glutathione S-transferase pull-down experiments. Taken together, the data suggest that PPAR␥ inhibits TGF-␤-induced CTGF expression in HASMCs by directly interfering with the Smad3 signaling pathway.

Osteoprotegerin (OPG) is a key regulator of osteoclastogenesis. Recent reports suggest that OPG may function as a protector of arterial calcification and survival of endothelial cells. However, the role and expression of OPG in vascular wall is unclear. Here we report that OPG was highly expressed in vascular smooth muscle cells (VSMC) but not in endothelial cells. Platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, tumor necrosis factor K K and interleukin-1L L upregulated OPG expression in VSMC. Moreover, inhibition of phosphatidylinositol 3-kinase/Akt or P38-signal pathway abrogated PDGF-induced OPG expression. Our results suggest that OPG may be an important determinant of vascular homeostasis. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

U-BIOPRED cohort n=91 epithelial brushings or biopsies IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype From a the Respiratory,