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.

Blume C, Davies DE (2013). In vitro and ex vivo models of human asthma. Eur J Pharm Biopharm. 84(2): 394-400. Read the paper

Swindle EJ, Davies DE (2011).  Artificial airways for the study of respiratory disease.  Expert Rev Respir Med. 5(6): 757-65. Read the paper 

Sun T, Swindle EJ, Collins JE, Holloway JA, Davies DE, Morgan H (2010).  On-chip epithelial barrier function assays using electrical impedance spectroscopy.  Lab Chip. 10(12): 1611-7. Read the paper 

Sun T, Tsuda S, Zauner KP, Morgan H (2010). On-chip electrical impedance tomography for imaging biological cells. Biosens Bioelectron. 25(5): 1109-15. Read the paper 

Swindle EJ, Collins JE, Davies DE (2009).  Breakdown in epithelial barrier function in patients with asthma: identification of novel therapeutic approaches. J Allergy Clin Immunol. 124(1): 23-34. Read the paper

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Project grant

Grant reference number

G0700636/1

Award date:

Apr 2008 - Aug 2010

Grant amount

£299,877