Human lung tissue for research on respiratory diseases

© Photo Fraunhofer ITEM

In-vitro models provide human physiology but have no organ functionality. Contrary to this, in-vivo models display organ functionality but no human physiology. Ex-vivo models maintain both aspects.

Some people try to breathe – but can’t. If the lung responds to harmless substances with a massive defense effort, this excessive immune response is termed allergic asthma. The results are constriction and inflammation of the airways down to the fine bronchioles and alveoli as well as bronchial hyperresponsiveness, which is the technical term for hypersensitivity to unspecific stimuli such as cold air.

The prevalence of allergic asthma has been increasing dramatically over the past few years. However, asthma is not the only disease on the rise: other life-threatening conditions of the respiratory tract, such as chronic obstructive pulmonary disease (COPD in short), pulmonary fibrosis, and infectious diseases are also gaining importance. At the same time, today’s drug development is facing a crisis: several million euros have to be invested in the development of a new pharmaceutical, but whether or not a drug candidate will ever reach market authorization remains open for a long time during the development process. In this context, it has become obvious that animal models are only of limited predictivity, which is why models that reflect essential elements of human pathology and are based on human cells and tissues (Fig. 1) need to be used as early as possible.

Fraunhofer ITEM has developed ex-vivo cultures of human explants and uses these for efficacy testing of new drugs – in order that people can breathe according to their body’s needs.

Precision-cut lung slices (PCLS)

Ex-vivo lung explants are living, three-dimensional lung tissue slices, also referred to as precision-cut lung slices (PCLS). PCLS contain nearly all cells that are normally present in the lung, for example, epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, mast cells, and nerve fibers. The cells are biologically active, which means that they communicate with each other and respond to cell-specific stimuli.

Preparation of PCLS in the lab includes the following steps: The lung as an organ has no defined shape and is of a very soft consistency. Using a special method, its rigidity must be increased to allow for the tissue to be accurately cut into thin slices with a microtome. The tissue slices are subsequently cultured with drug candidates or test substances. After several hours or days, the tissue response can be observed. For example, the airways in the tissue slices may show microscopic alterations, or release of signaling molecules can be found. At Fraunhofer ITEM, we have many years of extensive, high-level experience. We are one of three laboratories worldwide that have standardized and validated this method – masterminded by Fraunhofer ITEM.  

Reducing animal experiments by means of human lung slices

© Photo Fraunhofer ITEM

Human PCLS are entirely in line with the 3Rs principle proposed by Russel and Burch: they help replace, reduce, and refine animal experiments. Although in the foreseeable future it will not be possible to completely renounce on animal experiments, alternative methods such as human precision-cut lung slices make it possible to cut down on animal experiments. This is why this method has already been awarded several animal protection prizes.

Fraunhofer ITEM in-vitro toxicology

Focus of Research "Non-animal toxicology testing"