European Respiratory Journal

Nuria Roldan, Aude Rapet, Giulia Raggi, Maxime Epars, Kleanthis Fytianos, Janick D. Stucki, Nicole Schneider-Daum, Claus Michael-Lehr, Hanno Huwer, Thomas Geiser, Olivier T. Guenat & Nina Hobi 

Abstract

Pulmonary inflammatory disease is a worldwide health burden. As a common hallmark, the integrity of the alveolocapillary barrier is compromised, causing infiltration of proinflammatory immune cells, edema, and impaired gas exchange. Limited therapeutic options are available for patients suffering from those diseases, such as acute respiratory distress syndrome, highlighting the need for new models that could provide a better alternative for patientโ€™s needs. 

The aim of this study was to reproduce the disruption of the epithelial/endothelial barrier in an advanced in vitro system, the lung-on-chip, integrating the immune component (peripheral blood mononuclear cells, PBMC), proinflammatory stimuli (bacterial lipopolysaccharide, LPS) and breathing mimicking mechanics. 

Our results show that paracrine cell-cell crosstalk between the immune component and the epithelial/endothelial barrier is sufficient to trigger barrier disruption upon proinflammatory stimulation. High proinflammatory cytokine release (IL-8) was associated with increased barrier permeability and reduced transepithelial electrical resistance after cotreatment with PBMCs/LPS or PBMC/LPS conditioned medium. LPS-activated endothelium enabled the attachment and transmigration of PBMCs in a perfused lung-on-chip membrane whereas cyclic stretch favored endothelial tightness (p<0.01). 

In this study, we developed an in vitro model of pulmonary inflammation that recapitulates epithelial/endothelial barrier disruption, immune cell recruitment and transmigration and physiologically relevant lung-mimicking mechanics. This system is a promising tool that may provide insights into new therapeutic targets and enable animal-free preclinical drug testing.

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