A tissue engineered model of the human asthmatic airway pathway

Professor Donna Davies, from the University of Southampton, received a project grant in 2008 to develop a human tissue-based integrated system for studying asthma without the use of animals. Professor Davies has since received additional funding from the NC3Rs to further develop the model.

Research details

Principal Investigator: Donna Davies, Professor of Respiratory Cell and Molecular Biology
Organisation: University of Southampton
Award: £299,875, in 2007, over 29 months
Title: A tissue engineered model of the human asthmatic airway pathway

Read more about Professor Davies' research

Case study

The UK’s annual healthcare cost for asthma is estimated to be £2.5 billion

Asthma is an inflammatory disease of the airways that results in recurring episodes of breathing problems such as coughing, wheezing, chest tightness, and shortness of breath. It affects 5.4 million people in the UK, and is responsible each year for 1,500 avoidable deaths, as well as 20 million lost working days. The annual UK healthcare cost for asthma is estimated to be £2.5 billion.

There is currently no cure for asthma. Other than one class of drug which inhibits a specific inflammatory pathway, and a therapy that targets specific allergic antibodies (providing some symptomatic relief for 1 to 2% of the asthma population), there have been no effective new treatments for asthma since the introduction of beta2 receptor antagonists and corticosteroids in the 1960s.

There has been poor clinical translation of drugs developed in animal models

A range of animal species from rodents to monkeys are used in asthma research to model the three key hallmarks of the disease: airway obstruction, airway inflammation, and airway hyper-responsiveness. The mouse is the most commonly used species although the structure of the mouse lung and mechanics of breathing differ markedly from that in humans. Mice also lack a cough reflex. Most models involve sensitisation of the mouse with an allergen such as ovalbumin, with a subsequent allergen challenge. This is classified as moderate severity under the Animals (Scientific Procedures) Act 1986 because of the respiratory distress caused.

Mouse models have provided important insights into the cellular, immunological and molecular changes that occur in asthma. Nevertheless, most drugs based on preclinical studies have shown little clinical benefit in human asthmatics and the utility of animal models is under increasing scrutiny by asthma researchers. In vitro and ex vivo approaches have been used but their utility is limited by the poor availability of tissue; the paucity of technologies to non-invasively monitor cell behaviour; and the lack of immune cells which are a critical component of the disease. Importantly, none of the currently available animal models or in vitro or ex vivo approaches are amenable to studying the complex interplay between genetic and environmental factors which are believed to cause asthma.

 

A novel tissue engineered model plus new technologies to study the human asthmatic airway

With NC3Rs research funding, Professor Donna Davies, University of Southampton, has developed tissue engineered models of the human airway, which are already providing an alternative to using animals in asthma research. These models have a number of advantages over traditional approaches in that they use human tissue and are therefore clinically more representative, particularly in terms of studying genetic and environmental influences.

The models use airway epithelia from healthy and asthmatic individuals, combined with dendritic cells – the ‘sentinels’ of the immune system. Recent evidence has suggested that asthma is triggered by mediators released from the airway epithelial cells in response to environmental factors such as viruses. The mediators in turn elicit an ‘allergic-type’ of immune response with the potential to lead to asthma. Using healthy and diseased tissue, the new models have been used to investigate this further by exposure to the common cold virus, which is a major trigger for the development of asthma in susceptible individuals.

Two new technologies have also been developed which have allowed the use of the human tissue models to be further optimised. The first is a miniaturised chip which can be used with electrical impedance spectroscopy to measure in real-time the barrier properties of the airway epithelia. The epithelium acts as a barrier preventing toxins, microbes and airborne irritants entering the lungs; the barrier is abnormal in asthmatics and this new technology will allow the effects of environmental factors, such as cigarette smoke, on the epithelial barrier function to be assessed. The electrical impedance monitoring has been also been integrated with a microfluidics system which allows continuous replenishment of the cell culture medium, improving cell viability for long term studies and enabling continuous monitoring of soluble inflammatory mediators released by cells in response to environmental insult.

Moving beyond proof-of-principle

This grant has provided proof-of-principle for an integrated system for studying asthma without the use of animals. It has resulted in three publications to date. Based on the new model, three new grants have been awarded to Professor Davies; a strategic award from the NC3Rs to further develop the microfluidic system to enable other cell types to be incorporated into the model, an MRC programme grant and an MRC industrial collaborative CASE studentship, to use the microfluidic technology to study epithelial/dendritic cell interactions in asthma pathogenesis.

This case study was published in a review of our research portfolio in September 2011.