Interorgan Communication Between Lung and Colorectal Epithelial Cells Studied Using a Novel Multi‐Organ‐On‐Chip System

Chronic Obstructive Pulmonary Disease (COPD), a severe lung disease caused by chronic inhalation of toxic gases and particles, is often accompanied by extrapulmonary comorbidities. These are characterized by systemic inflammation and activation of the bi-directional lung-gut axis, in which communication takes place between lung and intestinal cells. The mechanisms of interorgan communication in COPD are largely unknown, partly due to the lack of suitable in vitro models to study interorgan communication. In the current study, we developed a novel unidirectional millifluidic multi-organ-on-chip (MOoC) device, in which stimulated lung epithelial cells were connected to colorectal cells. Human lung epithelial A549 cells were exposed to cigarette smoke extract and nylon microplastic fibers, mimicking inhaled pollutants that induce lung epithelial damage and can contribute to the development of COPD. Once exposed, A549 cells were connected to naïve colorectal DLD-1 cells within our MOoC system to study interorgan communication mediated by released factors such as cytokines, chemokines, or Damage Associated Molecular Patterns (DAMPs). A549 cells treated with inhalable pollutants released communication mediators, such as the DAMP galectin-3. Naïve DLD-1 cells responded to these released factors from stimulated A549 cells by inducing pro-inflammatory responses, demonstrated by increased IL-6 mRNA expression and decreasing barrier integrity, as demonstrated by decreased CDH1 mRNA expression and delocalization from the cell membrane of E-cadherin and ZO-1 proteins. This study introduces a novel chip platform that can be used to study communication between cells derived from different organs. This study also provides relevant insight into the mediators involved in lung-gut axis communication.