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

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

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.

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.