Extra-cellular matrix inducible collagenase activity in asthma: a potential drug target against airway remodelling.

Lead Research Organisation: University of Nottingham
Department Name: School of Medicine

Abstract

Asthma effects more than 5 million people in the UK and is responsible for 70,000 hospital admissions and 13,000 deaths each year. Despite treatment many patients still experience significant symptoms. Patients with chronic asthma can develop structural airway changes called airway remodelling which increase the frequency and severity of their symptoms. Airway remodelling is not well counted by current asthma therapies and new approaches to treat remodelling are urgently required. Extracellular matrix proteins surround all cells providing support but also effecting cell function. In remodelling, excessive amounts of the extracellular matrix proteins collagen 1 and tenascin-C are deposited in the airways. We have shown that these proteins can cause increased expression of enzymes called MMPs. We think that MMP-1, made by smooth muscle cells in the airways in response to signals from collagen 1 and tenascin-C leads to increased airway contraction and asthma symptoms. In this study, we will examine how collagen 1 and tenascin-C act on smooth muscle cells to produce more MMP-1. Next, we will determine how these extracellular matrix proteins and MMP-1 lead to increased airway contraction in an experimental model of asthma. We will then confirm our findings in human asthma: we will use samples from people with no lung disease and compare them with patients with asthma, with mild and stronger airway narrowing in response to a standard asthma trigger. By studying the expression of MMP-1, collagen I and tenascin-C in the lungs of these patients and if they have more airway narrowing and worse asthma symptoms. We hope this study will provide potential new targets for drugs to treat airway remodelling, reduce asthma symptoms and improve quality of life for those with asthma.

Technical Summary

Despite current therapies, patients with asthma develop progressive structural airway changes termed airway remodelling leading to airflow obstruction, bronchial hyper responsiveness, and worsening asthma symptoms. Airway smooth muscle (ASM) hyperplasia and increased extracellular matrix deposition are key features of remodelling, with collagen I and tenascin-C particularly over expressed. We and others have shown that matrix factors enhance ASM proliferation, survival and strongly induce the expression of matrix metalloproteinase-1 (MMP-1), a collagenase causing increased airway contraction in model systems. Here we will test the hypothesis that collagen I and tenascin-C increase MMP-1 activity worsening airway responsiveness and asthma symptoms. Studies will be conducted in patients and primary ASM obtained from three groups: normal volunteers, those with asthma and mild BHR (methacholine PC20 5-8mg/ml) and those with asthma and moderate to strong BHR with a methacholine (PC20 less than 1mg). Patients will be evaluated for asthma control and airway function and will undergo bronchoscopy, bronchial washings and airway biopsy. ASM cells will be cultured from patients and used in the following studies. We will investigate the receptors and signalling pathways linking collagen I and tenascin-C to increased MMP-1 transcription, the proteases are responsible for MMP-1 activation and if this is different in asthma derived cells. To determine if enhanced MMP-1 activity increases airway contraction we will use a lung slice model. Lung slices from normal animals and those over-expressing MMP-1 will be treated with chronic allergen exposure to develop airway remodelling and the response to contractile agonists determined. Finally we will examine the effect of collagenase activity on airway contraction in human asthma: firstly by studying the expression and co-localisation of MMP-1, collagen I and tenascin C in the airways of patients with asthma by immunohistochemistry and in situ zymography. We will then examine if MMP-1 protein and collagenase activity in bronchial washings and biopsies are associated with airway reactivity as determined by bronchial reactivity and methocholine and peak flow variability using multiple logistic regression in different asthma phenotypes. The experiments will determine the role of these matrix factors in remodelling, particularly with regard to airway contraction and highlight targets for therapeutic intervention.

Publications

10 25 50
 
Description Editor in Chief Thorax
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact As Editor-in-Chief of Thorax (the official journal of the British Thoracic Society and 4th highest Respiratory Journal) we have completely revised the instructions for authors to emphasise scientific rigour with explicit guidelines for research of many disciplines.
URL http://thorax.bmj.com/pages/authors/
 
Description Collaborative Research and Development Scheme
Amount £83,713 (GBP)
Organisation East Midlands Medilink 
Department Healthcare & Bioscience iNet
Sector Public
Country United Kingdom
Start 10/2012 
End 03/2015
 
Description Collaborative Research and Development Scheme
Amount £68,713 (GBP)
Organisation East Midlands Medilink 
Sector Private
Country United Kingdom
Start 10/2012 
End 02/2015
 
Description MRC / University of Nottingham DTG
Amount £60,000 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 04/2016
 
Description MRC IMPACT DTP Studentship
Amount £0 (GBP)
Funding ID na 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 08/2021
 
Description MRC Project grant
Amount £434,116 (GBP)
Funding ID G1100163 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2012 
End 08/2015
 
Description MRC Project grant
Amount £600,000 (GBP)
Funding ID MR/M004643/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2018
 
Description MRC Project grant
Amount £200,000 (GBP)
Funding ID MR/M004643/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description ECM cross-linking in asthma 
Organisation University of Nottingham
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of models, techniques and cells to apply matrix cross linking expertise
Collaborator Contribution Use of ECM and cell models and assays. Expertise and advice. Closely phenotyped model cell lines.
Impact Meeting abstracts have been presented, a peer reviewed manuscript is being prepared.
Start Year 2017
 
Description Effect of asthma exacerbations on MMP-1 activation 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution WE are using samples from Prof Sebastian Johnston's viral asthma exacerbation study to examine the effect of exacerbations on MMP-1 activation and how this is related to bronchial hyperresponsiveness
Collaborator Contribution Prof Johnston's team are supplying clinical data and paired BAL samples in patients with asthma and control pre and post viral excerbations of asthma. We are measuring MMP-1 expression and activity in the samples
Impact None to date, work ongoing
Start Year 2014
 
Description Mathematical modelling of airway remodelling 
Organisation University of Nottingham
Department School of Mathematics Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Physiological measurement of human and murine airway peramenters to inform mathematical model
Collaborator Contribution Development of predictive mathematical model to predict dynamics of airway remodelling in response to exacerbations and inflammatory events.
Impact Outputs, abstracts at the American Thoracic Society, Airway smooth muscle young investigator meetings and mathematical modelling meetings. Research papers Chernyavsky IL, Croisier H, Chapman LAC, Kimpton LS, Hiorns JE, Phillips J, Brook BS, Jensen OE, Billington CK, Hall IP, Johnson SR. New strategies to control inflammation-driven airway smooth muscle remodeling in asthma: insight from a theoretical model. PLoS ONE. 2014;10.1371/journal.pone.0090162. Hill MR, Philp CJ, Billington CK, Tatler AL, Johnson SR, O'Dea RD, Brook BS . A theoretical model of inflammation and mechano-transduction driven asthmatic airway remodelling. Biomechanics and Modeling in Mechanobiology 2018. https://doi.org/10.1007/s10237-018-1037-4 Disciplines, respiratory medicine and mathematics.
Start Year 2014
 
Description Proteolytic activity in COPD airways,: use of human rhinovirus exacerbation model 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are measuring protease activities in human rhinovirus infective exacerbations of COPD to phenotype patients and exacerbation types.
Collaborator Contribution Prof SL Johnston's team are providing airway samples and clinical data from their human COPD exacerbation model.
Impact None yet
Start Year 2017