Study of pyroptosis in models of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is one of the most frequent complications of premature children. It is characterized by alveolar simplification, impairment of vascular angiogenesis, inflammation and, in rare cases, neurodevelopmental complications. Increased evidence exists that pyroptosis might play a pivotal role in the development of BPD. Pyroptosis can be defined as a controlled lytic cell death, characterized by cell swelling and release of cytosolic content. Pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18, are released during this process by the formation of gasdermin D (GSDMD) pores in the cell membrane. In this study, two models of pyroptosis in BPD are presented: a neonatal hyperoxia-induced rat BPD model and a three-dimensional lung organoid model treated with a bronchoalveolar lavage fluid (BALF)–like medium. The results show clear indications of pyroptosis activation in the neonatal rat hyperoxia-induced BPD model. In this context, the therapeutic potential of mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) was also evaluated, revealing a positive association between their activity and reduced pyroptosis. The preliminary results on lung organoids suggest the possible activation of pyroptosis also in this model. To replicate the injury observed in vivo, the organoids are treated with a BALF-like medium coming from a co-culture of alveolar epithelial cells and human foetal lung fibroblasts. To mimic the inflammatory conditions of BPD, the co-culture was previously stimulated with a pro-inflammatory cytokine mix. In conclusion, the replication of key pyroptosis features by the proposed three-dimensional in vitro model paves the way for its use as a platform for mechanistic studies of BPD disease.