Modelling the human asthmatic airway by tissue engineering

Asthma is a disorder in which the conducting airways contract too much and too easily, both spontaneously and on exposure to a wide range of stimuli. Asthma prevalence rates have been increasing worldwide, and currently 5.1 million people are affected in the UK. It is responsible for 1500 avoidable deaths, 20 million lost working days and symptoms costing £2.5 billions p.a. Despite the availability of guidelines for management, current therapy is failing to control symptoms for over half of people with asthma. Within the pharmaceutical industry, there has been a high dependency on use of in vivo animal models of allergic airway inflammation for identification of novel targets for therapeutic intervention in asthma. However, these have met with only limited success, possibly because the structure of the mouse lung and the mechanics of breathing differ markedly from that in humans, and most importantly, mice do not spontaneously develop asthma. Thus, while providing insight into selected pathways of allergy, these mechanisms fail to address local tissue susceptibilities that would explain why approximately 40-50% of the population are atopic whereas only 5-10% develop asthma. Since animal experiments fail to reproduce the complex interplay between genetic and environmental stimuli that together constitute human asthma, we have developed human disease tissue-based in vitro models of asthma, focussing on the airway epithelium. As the barrier to the environment, this structure is intimately involved in communicating with cells of the immune system with the potential to translate mucosal gene-environment interactions critical for the development of asthma. Our models have already led to identification of key lesions in the asthmatic epithelium such as a deficiency in interferon production in response to rhinovirus infection which may help explain virus-induced asthma exacerbations. However, currently these models are relatively simplistic, low throughput systems and are limited, not only by the availability of tissue, but also by the paucity of non-destructive and non-invasive tools to continuously monitor cell behaviour. Thus, we have engineered more complex cellular models and sensor technology platforms to enable interactive monitoring of epithelial barrier function in asthma. Our models incorporate bronchial epithelial cells with dendritic cells which function as sentinels of the immune system, connecting innate and adaptive immunity. By combining tissue engineering with an impedance monitoring system and microfluidics, we anticipate that it will be possible to develop platforms that can be automated and optimized for drug screening. These models have the potential to become the systems of choice for identifying disease targets, assessing responses to novel therapeutics and for evaluating potential toxicity, thereby reducing the need for animal experimentation in the future. Such a tissue engineering approach would be applicable to other diseases such as smoking-related COPD.

• Research Review 2011: A tissue engineered model of the human asthmatic airway pathway
• Further Funding: NC3Rs Strategic Grant, A tissue engineered construct to monitor mucosal immunity in asthma, January 2011, £499,713
• Further Funding: NC3Rs Strategic Grant, Use of Drosophila models to explore the function of asthma susceptibility genes, April 2015, £89,116