Modelling alveoli on a breathing lung-on-chip in health and disease

The pharmaceutical industry is in rising need for alternative methods that minimise animal testing during early drug development, mainly because of the poor transferability from animal to human, costs or ethical issues. However, traditional cellular models fail to reproduce essential physio-pathological, systemic and structural aspects. In this sense, organ-on-chips have emerged as advanced in vitro systems emulating organ microenvironment. Due to the complex architecture and dynamics of the lungs, a significant way of entry for pathogens and pharmaceutical agents, we aim to develop a robust and versatile breathing alveolar model on chip to mimic better the physio-pathological milieu. We used the new AX12 setup (based on Stucki et al. Scientific Reports 2018, 33:14359), which enables physiological stretch and aerosol exposure, to model (1) alveolar inflammation and (2) anti-inflammatory drug administration. To do so, we generated a human alveolar barrier by co-culturing alveolar epithelial cells (hAELVi; Kuehn et al. Altex 2016, 33(3):251-60) with monocyte-derived macrophages (THP-1). To induce inflammation, cells were incubated with lipopolysaccharide (LPS) during 24h in static and breathing conditions. After 6h of LPS initial exposure, the anti-inflammatory drug budesonide was administered. Cytokine release was analysed by FACS, showing an increase in proinflammatory cytokines upon LPS exposure, and TEER and confocal imaging were used to follow the integrity of the epithelial barrier. Promising results were obtained highlighting the potential of this model for emulating respiratory lung diseases and aerosol therapy.