Organ-on-a-chip modelling of respiratory-vascular cell-cell communication in Chronic Obstructive Pulmonary Disease (COPD)

Context: In the lung, airways and blood vessels work together to ensure effective gas exchange. Cigarette smoke and air pollution cause Chronic Obstructive Pulmonary Disease (COPD) which is characterised by progressive inflammation and narrowing of the airways. Subsequent thickening of intrapulmonary blood vessels leading to pulmonary hypertension is a common complication of this disease. COPD affects both respiratory and vascular compartments in the lung but interactions between these two systems are poorly understood. There is no cure for COPD despite extensive animal experimentation.

Challenge: Current pre-clinical models poorly reproduce human COPD and better research tools are needed.  New 3D culture devices called Organs-on-chips aim to reproduce key features of human organs and tissues to replace the use of animal experimentation in modelling of human diseases.

Our data: We have created the Respiratory-VAScular (REVAS) organ-on-a-chip model of respiratory-vascular cell-cell communication which facilitates the study of the effects of airway damage on the pulmonary vasculature. This model consists of a “respiratory chip” containing human small airway epithelial and endothelial cells and a “vascular chip” hosting pulmonary arterial endothelial cells, pericytes, fibroblasts and smooth muscle cells. A peristaltic pump actuates the flow of media through endothelial channels and air through epithelial channels. Exciting new data show that exposure of the respiratory chip to oxidative stress profoundly affects the vascular chip, inducing inflammatory and angiogenic activation of endothelial and other cell types. Importantly, the endothelial response is markedly aggravated in the presence of other cell types, highlighting the importance of using multicellular systems in disease modelling.

Project aims: 

1. To study effects of cigarette smoke and ambient particulate matter collected from London roadside sites on human respiratory and vascular cell responses in REVAS.
2. To identify key mediators linking respiratory cell damage with vascular dysfunction.
3. To validate the model with FDA-approved and new drug targets in COPD.

Outcome: This study will test applicability of REVAS in modelling of human COPD, thus replacing animal experimentation. The project will help delineate mechanisms of airway-vascular cell-cell communication, how these are impacted by known environmental stressor linked to COPD and identify new therapeutic approaches in this severe chronic lung disease.