Toxicology Letters
Nuria Roldan, Aude Rapet, Andreas O. Stucki, Giulia Raggi, Kleanthis Fytianos, Thomas Geiser, Nina Hobi & Olivier T. Guenat
Abstract
Acute lung injury (ALI) is a complex lung disease in which inflammation plays a central role. The disruption of the alveolar epithelial-endothelial barrier together with an exacerbated inflammatory response lead to influx of oedema fluid into alveoli impairing gas exchange and lung mechanics. Sepsis, a severe bacterial infection, is a known trigger of ALI. For this reason, a classical approach for in vitro and in vivo studies is employing lipopolysaccharide (LPS), a component from gram-negative bacteria cell wall, to stimulate the inflammatory response, immune cell infiltration and tissue damage.
In this work, our aim was to investigate the combined role of lung mechanics, often neglected in in vitro studies, and inflammatory cells on the integrity of the endothelial barrier. With that purpose, we have employed primary pulmonary endothelial cells from a human source to reconstruct the aforementioned barrier using a lung-on-chip, a microfluidic device that reproduces the breathing motion. This system accounts for mechanical cyclic strain and enables the perfusion of circulatory immune cells.
Our results show that upon challenging the endothelial cells with LPS, the presence of immune cells led to a greater inflammatory response compared to that of pulmonary endothelial cells alone, also in terms of barrier integrity. We additionally show that this effect was not only due to cell-cell crosstalk but also to the physical interaction between immune cells and the endothelial barrier.
In conclusion, our model provides proof of the determinant role of the immune system in ALI in physiologically-mimicking dynamic conditions. These findings constitute a step towards a more accurate and clinically relevant in vitro system which in the future, could represent an alternative to animal models to design novel therapeutic approaches and evaluate drug toxicity.
