Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET
Chih-Hsi S Kuo, Stelios Pavlidis, Jie Zhu, Matthew Loza, Fred Baribaud, Anthony Rowe, Ioannis Pandis, David Gibeon, Uruj Hoda, Ana Sousa, Susan J Wilson, Peter Howarth, Dominick Shaw, Stephen Fowler, Barbro Dahlen, Pascal Chanez, Norbert Krug, Thomas Sandstrom, Louise Fleming, Julie Corfield, Charles Auffray, Ratko Djukanovic, Peter J Sterk, Yike Guo, Ian M Adcock, Kian Fan Chung, U-BIOPRED Project Team, Chih-Hsi S Kuo, Stelios Pavlidis, Jie Zhu, Matthew Loza, Fred Baribaud, Anthony Rowe, Ioannis Pandis, David Gibeon, Uruj Hoda, Ana Sousa, Susan J Wilson, Peter Howarth, Dominick Shaw, Stephen Fowler, Barbro Dahlen, Pascal Chanez, Norbert Krug, Thomas Sandstrom, Louise Fleming, Julie Corfield, Charles Auffray, Ratko Djukanovic, Peter J Sterk, Yike Guo, Ian M Adcock, Kian Fan Chung, U-BIOPRED Project Team
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.
Keywords: MET; MMP10; asthma; eosinophil; mast cell.
© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
Source: PubMed