Alternatives for lung research: stuck between a rat and a hard place

The respiratory system acts as a portal into the human body for airborne materials, which may gain access via the administration of medicines or inadvertently during inhalation of ambient air (e.g. air pollution). The burden of lung disease has been continuously increasing, to the point where it now represents a major cause of human morbidity and mortality worldwide. In the UK, more people die from respiratory disease than from coronary heart disease or non-respiratory cancer. For this reason alone, gaining an understanding of mechanisms of human lung biology, especially in injury and repair events, is now a principal focus within the field of respiratory medicine. Animal models are routinely used to investigate such events in the lung, but they do not truly reproduce the responses that occur in humans. Scientists committed to the more robust Three Rs principles of animal experimentation (Reduction, Refinement and Replacement) have been developing viable alternatives, derived from human medical waste tissues from patient donors, to generate in vitro models that resemble the in vivo human lung environment. In the specific case of inhalation toxicology, human-oriented models are especially warranted, given the new REACH regulations for the handling of chemicals, the rising air pollution problems and the availability of pharmaceutically valuable drugs. Advances in tissue-engineering have made it feasible and cost-effective to construct human tissue equivalents of the respiratory epithelia. The conducting airways of the lower respiratory system are a critical zone to recapitulate for use in inhalation toxicology. Three-dimensional (3-D) tissue designs which make use of primary cells, provide more in vivo-like responses, based on the targeted interactions of multiple cell types supported on artificial scaffolds. These scaffolds emulate the native extracellular matrix, in which cells differentiate into a functional pulmonary tissue. When 3-D cell cultures are employed for testing aerosolised chemicals, drugs and xenobiotics, responses are captured that mirror the events in the in situ human lung and provide human endpoint data.