The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology
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Asthma is characterised by heterogeneous clinical phenotypes. Our objective was to determine molecular phenotypes of asthma by analysing sputum cell transcriptomics from 104 moderate-to-severe asthmatic subjects and 16 nonasthmatic subjects. After filtering on the differentially expressed genes between eosinophil- and noneosinophil-associated sputum inflammation, we used unbiased hierarchical clustering on 508 differentially expressed genes and gene set variation analysis of specific gene sets. ⋯ TAC3 had normal to moderately high sputum eosinophils and better preserved forced expiratory volume in 1 s. Gene-protein coexpression networks from TAC1 and TAC2 extended this molecular classification. We defined one Th2-high eosinophilic phenotype TAC1, and two non-Th2 phenotypes TAC2 and TAC3, characterised by inflammasome-associated and metabolic/mitochondrial pathways, respectively.
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Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-β/Smad signalling. We sought to define the role of heat shock protein (HSP)90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis. We investigated the effects of HSP90 inhibition in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis. ⋯ Co-immunoprecipitation revealed that HSP90β interacted with TGF-β receptor II and stabilised TGF-β receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice. In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.
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Randomized Controlled Trial Multicenter Study
Psychometric properties of the St George's Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis.
The St George's Respiratory Questionnaire (SGRQ) has been used to measure health-related quality of life (HRQoL) in patients with idiopathic pulmonary fibrosis (IPF). This analysis evaluated the psychometric properties of the SGRQ using data from 428 patients with IPF who participated in a 12-month, randomised, placebo-controlled phase II trial of nintedanib. Internal consistency (Cronbach's α) was 0.91 for SGRQ total and >0.70 for domain scores. ⋯ Construct validity of SGRQ total and domain scores was supported by weak to moderate cross-sectional correlations with the Medical Research Council dyspnoea scale (0.32-0.55), 6-min walk test distance (-0.25- -0.34), percentage predicted forced vital capacity (-0.11- -0.15) and measures of gas exchange (-0.26-0.03). There was some evidence that the SGRQ total score was sensitive to detecting change. The reliability, construct validity and responsiveness of the SGRQ in patients with IPF suggest that this is an acceptable measure of HRQoL in patients with IPF.
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Practice Guideline
European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.
The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. ⋯ It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.