Research Papers:
Largescale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells
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Elena Alexandrova1,2, Giovanni Nassa1, Giacomo Corleone1, Anton Buzdin3,4, Alexander M. Aliper3,4, Nadezhda Terekhanova4, Denis Shepelin4,5, Alexander Zhavoronkov6, Michael Tamm7, Luciano Milanesi8, Nicola Miglino7,*, Alessandro Weisz1,9 and Pieter Borger7,*
1 Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy
2 Genomix4Life Srl, Campus of Medicine, University of Salerno, Baronissi (SA), Italy
3 Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
4 Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR
5 Group for Genomic Regulation of Cell Signalling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
6 Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA
7 Department of Biomedicine, University Hospital Basel, Basel, Switzerland
8 Institute of Biomedical Technologies, National Research Council, Segregate, (MI), Italy
9 Molecular Pathology and Medical Genomics Unit, ‘SS. Giovanni di Dio e Ruggi d’Aragona - Schola Medica Salernitana’ University Hospital, Salerno, (SA), Italy
* These authors have contributed equally to this work
Correspondence to:
Pieter Borger, email:
Alessandro Weisz, email:
Keywords: asthma, smooth muscle cells, signalling pathways, CAGE
Received: December 07, 2015 Accepted: January 26, 2016 Published: February 05, 2016
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.