In a ground breaking development scientists have successfully modeled cystic fibrosis in human Lung Airway Chip – a breakthrough that will allow scientists to attack challenges that are important to CF patients.
Through the model scientists were able to replicate CF-specific changes in multiple hallmarks of the disease, including in the airway’s mucus layer, beating of mucus-transporting cilia, pathogen growth, inflammatory molecules, and the recruitment of white blood cells, providing a comprehensive preclinical human model in which to investigate new CF therapies.
To model and compare the microstructure and function of vascularized CF airways researchers grew lung airway cells obtained from human CF patients or healthy individuals in one of two parallel running hollow channels of a microfluidic device under air, recapitulating the lung’s air-transporting environment. In the second channel, which is separated from the first one by a porous membrane, they recreated a human blood vessel from human lung microvascular cells that was perfused with a blood substitute medium.
After culturing the Airway Chips for two weeks, the researchers measured the levels of pro- and anti-inflammatory factors flowing out of the Airway Chip’s vascular channel that are known to be involved in the inflammatory response in the lungs of CF patients. Among other changes, the level of the pro-inflammatory cytokine IL-8 was increased in CF chips compared to those in control Airway Chips. Interestingly, IL-8 is known for its ability to attract the type of white blood cells know as neutrophils that also drive inflammation in the lungs of CF patients.
When the researchers then actually flowed human neutrophils through the vascular channel of the CF Airway Chips, they observed that more of the immune cells spontaneously adhered to the surface of vascular cells, squeezed themselves through the vascular cell layer and porous membrane, and accumulated in the airway epithelial cell layer of the air channel – recapitulating a process known as “transmigration.”
But the CF-mimicking airway tissue not only stimulated immune cell recruitment, it also supported the growth of the bacterium, Pseudomonas aeruginosa, which is present in the microbiome of normal lung but can grow out of control and cause lung infections in human CF patients. Twenty-four hours after they introduced a fluorescently labeled version of P. aeruginosa into the airway channel of chips created with bronchial epithelial cells from CF patients, the team detected higher numbers of the pathogen in CF-specific mucus than in mucus in healthy Airway Chips. As a consequence, the levels of pro-inflammatory cytokines were further increased, thus replicating the infection-inflammation cycle seen in CF patients.
As next steps, the team will further personalize their CF Lung Airway Chip by generating versions in which bronchial epithelial, vascular endothelial, and immune cells all are obtained from the same patient.