title: Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells.
abstract: BACKGROUND
  Bronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive ("primed") phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. This "primed" phenotype helps to understand pathogenesis of asthma, as changes in BSM function are essential for manifestation of allergic and inflammatory responses and airway wall remodelling.
  
  
  OBJECTIVE
  To identify signalling pathways in cultured primary BSMs of asthma patients and non-asthmatic subjects by genome wide profiling of differentially expressed mRNAs and activated intracellular signalling pathways (ISPs).
  
  
  METHODS
  Transcriptome profiling by cap-analysis-of-gene-expression (CAGE), which permits selection of preferentially capped mRNAs most likely to be translated into proteins, was performed in human BSM cells from asthmatic (n=8) and non-asthmatic (n=6) subjects and OncoFinder tool were then exploited for identification of ISP deregulations.
  
  
  RESULTS
  CAGE revealed >600 RNAs differentially expressed in asthma vs control cells (p≤0.005), with asthma samples showing a high degree of similarity among them. Comprehensive ISP activation analysis revealed that among 269 pathways analysed, 145 (p<0.05) or 103 (p<0.01) are differentially active in asthma, with profiles that clearly characterize BSM cells of asthmatic individuals. Notably, we identified 7 clusters of coherently acting pathways functionally related to the disease, with ISPs down-regulated in asthma mostly targeting cell death-promoting pathways and up-regulated ones affecting cell growth and proliferation, inflammatory response, control of smooth muscle contraction and hypoxia-related signalization.
  
  
  CONCLUSIONS
  These first-time results can now be exploited toward development of novel therapeutic strategies targeting ISP signatures linked to asthma pathophysiology.
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.|Genomix4Life Srl, Campus of Medicine, University of Salerno, Baronissi (SA), Italy.
authors: Elena
authors: E
authors: Alexandrova
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors: Giovanni
authors: G
authors: Nassa
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors: Giacomo
authors: G
authors: Corleone
authors: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
authors: Anton
authors: A
authors: Buzdin
authors: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
authors: Alexander M
authors: AM
authors: Aliper
authors: Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
authors: Nadezhda
authors: N
authors: Terekhanova
authors: Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Group for Genomic Regulation of Cell Signalling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors: Denis
authors: D
authors: Shepelin
authors: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
authors: Alexander
authors: A
authors: Zhavoronkov
authors: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors: Michael
authors: M
authors: Tamm
authors: Institute of Biomedical Technologies, National Research Council, Segregate (MI), Italy.
authors: Luciano
authors: L
authors: Milanesi
authors: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors: Nicola
authors: N
authors: Miglino
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.|Molecular Pathology and Medical Genomics Unit, 'SS. Giovanni di Dio e Ruggi d'Aragona - Schola Medica Salernitana' University Hospital, Salerno (SA), Italy.
authors: Alessandro
authors: A
authors: Weisz
authors: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors: Pieter
authors: P
authors: Borger
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome; D055815:Young Adult
keywords: CAGE; asthma; signalling pathways; smooth muscle cells