Researchers at the Wyss Institute have made significant progresses in this direction. In a recent study led by Donald E. Ingber and his team, they presented a microfluidic organ-on-a-chip designed to model acute RILI in vitro. This 'Lung Alveolus Chip' is lined with human lung alveolar epithelium interfaced with pulmonary endothelium. When exposed to gamma radiation, this chip shows signs of RILI within 6 hours, with both the lung epithelium and endothelium exhibiting DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and a loss of barrier function. Interestingly, the radiation dose sensitivity observed on this chip is more consistent with the human lung than traditional animal preclinical models.

The challenge with RILI is that its onset is sudden and severe, typically occurring 1-3 weeks post-exposure. Symptoms include shortness of breath, dry cough, fever, and chest pain. Presently, the primary treatment for RILI is prolonged therapy with glucocorticoids like prednisolone, aiming to reduce inflammation. However, there's limited evidence to support its effectiveness in mitigating pneumonitis, making the search for better treatments a priority. Considering the ethical implications and feasibility concerns of clinical studies on radiation exposure, researchers have had to rely on animal models to understand RILI. Unfortunately, these models, including mice and non-human primates, often fail to capture the clinical relevance and key hallmarks of human pathophysiology. This is where the Wyss Institute's Lung Alveolus Chip comes into play.

The chip mimics the human lung's response to radiation exposure, making it a valuable tool for studying RILI's molecular basis. To develop this model, the researchers used the organ-on-a-chip microfluidic culture technology. Such Organ Chip models have previously been employed to study various lung diseases, including asthma, COPD, and lung cancer. The Lung Alveolus Chip, in particular, contains primary human lung alveolar epithelial cells and is designed to simulate the conditions of a real human lung, right down to mimicking breathing motions.

In their experiments, the researchers found that the chip could replicate many of RILI's physiological hallmarks when exposed to clinically relevant radiation doses. This paves the way for a deeper understanding of how radiation affects the human lung at the cellular and molecular levels, potentially leading to more effective treatments and interventions.

A human lung alveolus-on-a-chip model of acute radiation-induced lung injury

Queeny Dasgupta, Amanda Jiang, Amy M Wen, Robert J Mannix, Yuncheng Man, Sean Hall, Emilia Javorsky, Donald E Ingber.