Department for BioMedical Research (DBMR)

Lung Precision Medicine - LPM

Blank Lab

Ongoing Projects

A regulatory step towards 3R: Refinement of in vitro – in vivo extrapolation (IVIVE) for predictive inhalation toxicology (NRP79)

In the field of inhalation toxicology, animal testing is still standard for the risk assessment of chemicals and materials, as well as for testing new drugs. This project aims to optimize and standardize human 3D lung cell models to predict the effects of inhaled substances.

The development of innovative in vitro lung cell culture models has made great progress in recent years. The significance of these models regarding health effects in humans or animals must urgently be examined in more detail to enable extrapolation of the in vitro results to the in vivo situation (IVIVE) and to ultimately strengthen the acceptance of these models as a validated alternative to animal experiments in the field of inhalation toxicology. In this project, we analyze the effects of inhaled materials in animals and in 3D lung models using the so-called “adverse outcome pathway” concept. This approach describes biological processes that lead to a disease and significantly helps to improve the informative value of 3D lung cell models. In this concept, we use (nano)materials for which biological processes in connection with health-endangering effects have already been described in animal models. We are optimizing established and well-characterized in vitro 3D lung models and carry out limited animal experiments to precisely simulate in vivo effects. Finally, we test the in vitro 3D lung models using standardized protocols, run tests with various laboratories and write recommendations for alternative methods to animal testing studies. The continued development and characterization of existing but not yet pre-validated in vitro models will enable us to reproducibly predict the effects of inhaled substances and to reduce animal testing. The approach for optimized IVIVE and development of standard protocols can also be applied to other pre-validated tissue models.

Outline of approach for IVIVE: Screening of biomarkers according to the adverse outcome pathway as described in the OECD giuideline s

Translocation and health effects of inhaled micro- and nanoplastic

Recent studies have demonstrated the persistence of micro- and nanoplastics (MP/NP) of different origins and different sizes in human pulmonary tissue. A considerable fraction of inhaled MP/NP may avoid pulmonary clearance and prolong interaction with cells of the respiratory tract. Thus, MP/NP potentially accumulate and persist in the human lungs for a long time, which might induce continuous adverse effects, such as oxidative damage caused by ROS or chronic inflammation which may lead to fibrosis in the lungs. Though, there is an increasing number of studies dealing with potential health effects of inhaled MP/NP, there is still considerable lack of knowledge regarding translocation and interaction of those particles with the pulmonary immune system, depending on material, surface composition (e.g. coating) and size.

In this project, we aim to study the effect of polystyrene, polyethylene, and polyethylene terephthalate MP/NP, from controlled production and thoroughly characterized regarding size distribution, shape, and surface characteristics on the human respiratory tract. We are employing advanced in vitro models of the human airways and gas exchange region (primary epithelial cells, macrophages dendritic cells, or cell lines grown at the air-liquid interface) to study the exposure to MP/NP.

Confocal laser scanning micrograph of primary human nasal epithelial cells (actin, green) exposed to 1m polystyrene particles (red), nebulized at the air-liquid interface employing the Vitrocell System. Particles are trapped inside a thick layer of mucus (MUC5AC, yellow). Upper panel: xy-projection; lover panel: xz-projection