Chih-Hsi S Kuo1,2,3, Stelios Pavlidis3,4, Jie Zhu1, Matthew Loza4, Fred Baribaud4, Anthony Rowe4, Ioannis Pandis1,2, David Gibeon1,2, Uruj Hoda3, Ana Sousa5, Susan J Wilson6,7, Peter Howarth6,7, Dominick Shaw8, Stephen Fowler9, Barbro Dahlen10, Pascal Chanez11, Norbert Krug12, Thomas Sandstrom13, Louise Fleming3, Julie Corfield14,15, Charles Auffray16, Ratko Djukanovic6,7, Peter J Sterk17, Yike Guo3, Ian M Adcock1,2, Kian Fan Chung1,2. 1. Airways Disease, National Heart & Lung Institute, Imperial College, London, UK. 2. Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, UK. 3. Department of Computing & Data Science Institute, Imperial College, London, UK. 4. Janssen Research and Development, High Wycombe, UK. 5. Respiratory Therapeutic Unit, GlaxoSmithKline, Stockley Park, UK. 6. Faculty of Medicine, Southampton University, Southampton, UK. 7. NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK. 8. Respiratory Research Unit, University of Nottingham, Nottingham, UK. 9. Centre for Respiratory Medicine and Allergy, The University of Manchester, Manchester, UK. 10. The Centre for Allergy Research, The Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. 11. Laboratoire d'immunologie, Département des Maladies Respiratoires, Aix Marseille Université Marseille, Marseille, France. 12. Immunology, Allergology and Clinical Inhalation, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. 13. Department of Medicine, Respiratory and Allergy unit, University Hospital, Umeå, Sweden. 14. AstraZeneca R & D, Molndal, Sweden. 15. Areteva R & D, Nottingham, UK. 16. European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon, Lyon, France. 17. Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherland.
Abstract
BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
Authors: Lorenza Vantaggiato; Paolo Cameli; Laura Bergantini; Miriana d'Alessandro; Enxhi Shaba; Alfonso Carleo; Fabrizio Di Giuseppe; Stefania Angelucci; Guido Sebastiani; Francesco Dotta; Luca Bini; Elena Bargagli; Claudia Landi Journal: Biomedicines Date: 2022-03-24