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bioRxiv · 10.1101/2023.02.13.528339

Hemoxygenase-1 as a key mediator of acute radiation pneumonitis revealed in a human lung alveolus-on-a-chip

Dasgupta, Q.·Jiang, A.·Hall, S.·Mannix, R.·Wen, A. M.·Ingber, D. E.
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Abstract

Exposure to gamma radiation either due to environmental disasters or cancer radiotherapy can result in development of acute radiation syndrome (ARS), characterized by pneumonitis and lung fibrosis. We leveraged a microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium to model acute radiation-induced lung injury in vitro. Both lung epithelium and endothelium exhibited DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6 h of radiation exposure, although greater damage was observed in the endothelium. Transcriptomic analysis revealed increased expression of the cytoprotective gene, hemoxygenase-1 (HMOX-1) and gene network analysis identified it as a central mediator of radiation-induced injury. Pharmacological stimulation of HMOX-1 activity also significantly reduced acute radiation-induced lung injury, although it enhanced damage at later times. Thus, this human lung chip offers a new platform to study ARS and these results suggest that HMOX-1 may be mechanistically involved in this injury response.

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Dasgupta, Q., Jiang, A., Hall, S., Mannix, R., Wen, A. M., Ingber, D. E.. 2023-02-13. Hemoxygenase-1 as a key mediator of acute radiation pneumonitis revealed in a human lung alveolus-on-a-chip. https://doi.org/10.1101/2023.02.13.528339

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