Interactions of mechano-transduction and inflammatory pathways in asthmatic airway remodelling: in silico, in vivo and in vitro models.

Lead Research Organisation: University of Nottingham
Department Name: Sch of Mathematical Sciences

Abstract

Asthma is a chronic disease that affects the airways that carry air in and out of the lungs. It affects ~300m people worldwide, and in the UK costs the NHS £2.3billion a year with 80% of this expenditure spent on the 20% of patients with the most severe and poorly controlled asthma.

During an asthma attack, triggered by irritants such as dust or smoke, the muscle cells that line the walls of the airways, contract so that the airway becomes narrower. This is called bronchoconstriction. The lining of the airways also becomes inflamed and sticky mucus or phlegm is produced. All these reactions cause the airways to become narrower and irritated, leading to the symptoms of asthma such as coughing and wheezing. Over time, repeated episodes of asthma attacks can cause the number of muscle cells and other cells in the airway wall to increase resulting in the airway wall getting thicker (called remodelling) thereby exacerbating asthma symptoms and causing a decline in lung function. Doctors are currently unable to prevent airway remodelling or reverse it once it has occurred. Although symptoms can be managed with regular medication, serious complications can still arise requiring hospitalisation. For a very long time inflammation was thought to be the main cause of remodelling. However, medication called corticosteroids, that keeps inflammation levels down, in many cases appear to have little effect in preventing remodelling. More recently, we and others have found that, instead, bronchoconstriction itself may cause remodelling. Given that bronchoconstriction and inflammation occur together in asthma, we suggest a new theory: while remodelling might be initiated by inflammation, the contraction of the airway during bronchoconstriction, generates forces that trigger cells to produce chemicals that cause the airway wall to become even thicker. The increased numbers of cells respond even more strongly to inflammation so that there is a worsening cycle.

Our aim is to investigate the combined effect of both inflammation and bronchoconstriction (which occur over minutes to hours) on remodelling which occurs over longer periods of time (days to weeks). The problem is very complex because there are both mechanical and biochemical processes involved that probably feedback on each other, as well as many cell types contained in the airway wall that also interact. Much of the research so far has been carried out on these individual aspects but it is incredibly difficult to work out what the combined effect of these interactions are, just by looking at the individual measurements.

This work will develop a new model that represents both the biochemical and mechanical processes involved, and their complex interactions. This will allow us to run computational simulations for many random asthma episodes to predict whether or not remodelling occurs. To develop this model we will combine cutting-edge physics, mathematics and biological information from experiments on both human and animal tissue, bridging the gaps between the different levels (cells to tissues). This work will require both theoretical and experimental scientists to work as a team to ensure that the experiments that are done are designed in such a way that the theoretical models can be developed with exactly the right kind of data. Once the models are developed, they will need testing to ensure that what the model predicts matches what happens in real airways. So other data from specially designed experiments will also used for model testing.

This work will thus help us to understand how the processes involved in remodelling interact with each other, and so to understand what might happen if we could disrupt one of the processes. Ultimately, computational tools developed in this way will help scientists really understand the underlying biology and to find new, more effective, therapies to either stop or reverse airway remodelling, preventing further decline in lung functio

Technical Summary

Inflammation has long been considered the main process by which airway remodelling in asthma occurs, supported by in vitro and animal studies. We, and others have shown that, instead, bronchoconstriction can promote airway remodelling independent of inflammation. These findings motivate the need to better understand how the mechanisms of inflammation and bronchoconstriction might be intertwined. Our recent work in computational airway biology leads to our central hypothesis: while airway remodelling might be initiated by inflammatory cytokines, it is perpetuated by mechanical factors.

Our aim is thus to investigate the combined effect of repeated, short term, inflammatory episodes and associated mechanical forces arising from ASM contraction on long-term airway remodelling. The complexity of the bio-chemical and mechanical processes involved, over many space and time-scales, precludes identification of dominant interactions from experiments on isolated processes. We will therefore develop a quantitative modelling framework accounting for biochemical and mechanical processes at cell and tissue levels, informed by appropriate in vitro and in vivo studies. This unprecedented approach will combine mechanisms hitherto neglected in investigations of airway remodelling. In particular we will address:(i) The role of TGF-beta signalling on ASM/ECM structural changes;(ii) The role of mechanical factors in long-term structural changes; (iii) Accurate quantification of rates of apoptosis, proliferation, migration, inflammation resolution within the in vivo micro-mechanical environment.

A vital aspect of this work will be an iterative process in which data from sophisticated experiments will enable refinement of models and models will influence experimental design, leading to synergistic evolution of both. The proposed work will result in a systems biology toolset that will be of benefit to the medical community in finding effective anti-remodelling therapies for asthma.

Planned Impact

Asthma is a chronic disease characterised by inflammation, airway hyper-responsiveness and airway remodelling. It affects ~300m people globally and has an annual financial burden of £2.3billion in the UK. Importantly 80% of this expenditure is spent on the 20% of people with the most severe and poorly controlled asthma. Bronchodilators and inhaled corticosteroids have limited therapeutic benefit in this sub-group of patients impacting severely on the quality of life for these patients. Therefore understanding the pathogenesis of chronic asthma and identifying new targets that can arrest disease progression will significantly impact on the lives of all asthma patients. Given the rising prevalence of (childhood) asthma a significant percentage of the population can directly relate to it. This provides an ideal opportunity to promote scientific advances in asthma research to the wider public and to increase awareness of the benefits of multidisciplinary approaches in unravelling the causes of chronic asthma showcasing the predictive power of theoretical integrative physiology.

The causes of disease progression over the lifetime of a patient with asthma are poorly understood, with current therapies proving to be ineffective in certain sub-groups of patients. A validated, more realistic, mechanobiological model of airway remodelling will significantly contribute towards identification of new targets and hence drug development for arresting disease progression. By simulating the action of potential novel drugs, ineffective compounds can be ruled out at early stages, thus considerably reducing the costs of drug development. Simulations will also reduce the number of animal experiments to be conducted. This will again help to cut cost, and concomitantly improve the quality of animal welfare. The proposed development of a multi-scale spatio-temporal model of airway remodelling will aid in the development of a systems biology toolset that will enable experimentalists to test hyphotheses leading to advances of genuine physiological relevance. Since models, both at the cellular and tissue level, are readily adaptable to latest patient data, predictions of disease progression based on individual patient history will provide important guides for developing stratified treatment plans. Ultimately this will lead to a systems medicine testbed allowing clinicians to understand disease progression in particular patient sub-groups enabling development of optimally stratified treatment strategies. Predictive models will assist decision makers to coordinate the most effective approach to tackle disease progression in asthma helping to ease the financial pressure on public healthcare expenditure.

The PDRAs to be employed will acquire skills in advanced mathematical modelling, highly transferable computationally intensive methods (Compucell3d, Chaste), novel in vitro and in vivo experimental techniques that will be transferable to many other areas of biomolecular chemistry and imaging of cells and tissues. In addition to independent working, time management and project organisation, the PDRAs will develop presentation and communication skills, presenting at both clinical and modelling conferences. Furthermore it will provide them with unique skillsets that come from working as part of a multi-disciplinary team. All these, combined with the wide range of supplementary courses on offer within the University, and elsewhere (British Science Association, Royal Society) will positively impact on the future career prospects of the PDRA. The PI, Co-Is and external partners will benefit by establishing fruitful collaborations between disciplines in the life and physical sciences.

Publications

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Naveed SU (2017) Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity. in American journal of respiratory and critical care medicine

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Maarsingh H (2019) Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices. in American journal of physiology. Lung cellular and molecular physiology

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John AE (2017) Methods for the Assessment of Active Transforming Growth Factor-ß in Cells and Tissues. in Methods in molecular biology (Clifton, N.J.)

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Brook B. S. (2016) The Impact Of Bronchial Thermoplasty On Airway Epithelial And Smooth Muscle Cells: An In Vitro And In Silico Study in AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

 
Description Birmingham - Diamond Collaboration
Amount £36,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 02/2020 
End 03/2020
 
Description IMPACT Doctoral Training Partnership
Amount £84,257 (GBP)
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 03/2021
 
Description UK Multiscale Biology Network -support for new collaborations
Amount £1,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 05/2018
 
Title Automated immunohistochemistry image-processing 
Description This is a computational tool developed to semi-automatically detect airway objects, and stained constituents such as airway smooth muscle and collagen. This allows quantification of upwards of 500 airways within a single mouse lung. This will improve robustness and reproducibility of the data due to the large n-numbers available. 
Type Of Material Computer model/algorithm 
Year Produced 2016 
Provided To Others? Yes  
Impact This has significantly reduced the amount of time taken to examine images from immunohistochemistry slides. We will be publishing the data using these automated microscopy tools in the near future. 
 
Title Morphoelastic models of inflammation-driven airway remodelling 
Description Inflammation is known to drive structural changes in the airway wall (such as increased airway smooth muscle mass and collagen deposition). We have developed a morphoelastic model in which ASM proliferation/recruitment and collagen deposition is driven by periodic inflammatory events. 
Type Of Material Computer model/algorithm 
Provided To Others? No  
Impact WE will use this model in a multi-scale model being developed in the EU project AirPROM to predict outcomes of a clinical trial in which PGD2 receptors are inhibited. 
 
Description Integrin-mediated force transmission 
Organisation University of Missouri
Department Medical Pharmacology and Physiology
Country United States 
Sector Hospitals 
PI Contribution My PhD student Linda Irons and I have been working with Prof Meininger at the above institution to develop models of integrin-mediated force transmission in parallel with atomic force microscopy (AFM) experiments at Prof Meininger's lab. Additionally, my post-doc Michael Hill spent a month on secondment at Prof Meininger's lab to investigate organisation of airway smooth muscle and extracellular matrix in an intact airway using advanced imaging techniques.
Collaborator Contribution Prof Meininger and his team have carried out a number of AFM experiments to provide us with data for our models. They have also hosted a visit from my postdoc and provided him with training in advanced histomorphology and imaging techniques.
Impact Multidisciplinary collaboration involving mathematical and computational modelling, atomic force microscopy to measure cell-cell and cell-ECM adhesion and advanced imaging. Three abstracts have been submitted and accepted at the following meetings: Experimental Biology, Chicago, 2017 Annual Linz Winterworkshop. Advances in Single-Molecule Research for Biology & Nanoscience, 2017 Joint Annual Conference of British Microcirculation Society and UK Cell Adhesion Society, Birmingham, UK, 2017
Start Year 2015
 
Description Lung modelling working group 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributing to a lung modelling working group in which we are working toward putting together an EPSRC networking bid to facilitate collaborations between mathematical modellers and respiratory clinicians to study respiratory diseases (asthma, COPD, cystic fibrosis).
Collaborator Contribution Our partners are leading the working group and the EPSRC bid
Impact No outputs yet. The collaboration is multi-disciplinary and involves mathematical and computational modelling, experimental biology, clinical respiratory physiology.
Start Year 2020
 
Description Asthma stall at Science in the Park 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Had a stall at a science fair called Science in the Park. Stall was titled the "Mathematics of Asthma". Myself and two of my PhD students talked to families (usually a couple of parents or grandparents and 1/2/3 school age children, explaining what happens during an asthma attack using hands-on demonstrators . They then could do an "experiment" using springs and weights to show how mechanical properties of biological tissues can be represented by springs and how we can learn about biology by developing mathematical models. We spoke to approximately 120 individuals and about 30 of the children left feedback - a sentence or two on post-it notes saying what they learnt from the activity. A large number of them either suffered from asthma or knew people who did.
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/events/579480322497649/?active_tab=discussion
 
Description Asthma stall at Wonder (University of Nottingham Science fair) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Had a stall at Wonder (a science fair organised by University of Nottingham). Stall was titled the "How does Asthma add up?". Myself and two of my postdocs talked to families (usually a couple of parents or grandparents and 1/2/3 school age children, explaining what happens during an asthma attack using hands-on demonstrators . They then could do an "experiment" using springs and weights to show how mechanical properties of biological tissues can be represented by springs and how we can learn about biology by developing mathematical models. We spoke to approximately 120 individuals and about 30 of the children left feedback - a sentence or two on post-it notes saying what they learnt from the activity. A large number of them either suffered from asthma or knew people who did.
Year(s) Of Engagement Activity 2019
URL https://www.nottingham.ac.uk/wonder/
 
Description Cub scout talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact On 8th March 2016, CKB held an interactive session at the 124th Derby Scouts group explaining the importance and potential of maths in medicine with particular emphasis on our asthma-related project. 22 scouts and 3 leaders attended.
Year(s) Of Engagement Activity 2016
 
Description Local school visit to the University for a Masterclass as part of the Ambition Nottingham programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 55 6th Formers attended a Maths Masterclass at the University of Nottingham as part of the Ambition Nottingham programme. I gave an interactive presentation about my research using mathematics to understand asthma. Survey results still to come but some individual comments included below:
'Clearly explained and very interactive!! Was fun with the paper and weights'
'Really enjoyed it - the linking of maths to biology was great as this isn't often mentioned. The lecturers were nice and informative'
'The speakers are passionate about the subject and it showed in their deliveries. Interesting to learn about real life applications of maths'
Year(s) Of Engagement Activity 2019
URL https://www.nottingham.ac.uk/schoolsliaison/services/ambition-post-16.aspx
 
Description School Visit (Firbeck Academy Nottingham) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Organised an activity at the Firbeck Academy Wow day. Approx 60 pupils participated in my event, and 4 teachers/teaching assistants and 4 university undergraduate students helped run the activity with me. It sparked questions and discussion afterwards, and the school teachers reported back on how interesting/exciting the pupils had found it.
Year(s) Of Engagement Activity 2017
URL https://www.nottingham.ac.uk/news/pressreleases/2017/december/firbeck-students-get-hands-on-to-inspi...
 
Description School visit (Kesteven and Grantham Girls School) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I presented a talk to 6th formers who are making decisions about University applications. It was about where Mathematics can take you post University and I described my own research into using mathematics to understand asthma. A survey after the talk indicated the following: 7 out of 19 students said that after the talk they are more likely to consider a university course in a related area, 10 said they were already considering it and 2 said they were unsure
Year(s) Of Engagement Activity 2019
 
Description University of Nottingham Mayfest 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact On 9th May 2015 UoN held MayFest, an outreach event attended by ~3000 people. CKB helped run the Div. Respiratory Medicine stand where, amongst many lung-related activities the disease-induced changes in airway structure were shown to people using human tissue sections.
Year(s) Of Engagement Activity 2015,2016