Caspase-8-driven NLRP3 inflammasome activation exacerbates bronchopulmonary dysplasia by increasing the apoptosis and pyroptosis crosstalk of alveolar epithelial cells.

BACKGROUND

The programmed cell death (PCD) of alveolar epithelial cells, which is mediated by inflammation and oxidative stress, plays an important role in the development of bronchopulmonary dysplasia (BPD). Caspase-8 is an important molecular switch that regulates PCD; however, its mechanism of mediating pyroptosis in BPD remains unclear.

METHOD

We respectively established an in vitro and in vivo BPD model by stimulating human lung epithelial cells (BEAS-2B) and neonatal mice with hyperoxia exposure. These models were administered a caspase-1 inhibitor, caspase-8 inhibitor, or a combination to investigate the effects of caspase-8 on BPD pyroptosis, alveolar development, immune cell recruitment, and pulmonary vascular remodeling.

RESULTS

The expression and activity of caspase-8 are significantly increased in BPD mice. Caspase-8 inhibition attenuates the activation of the NLRP3 inflammasome, and reduces the expression of the pyroptosis-related proteins caspase-1, gasdermin-D (GSDMD), and ASC. Caspase-8 inhibition reduces the recruitment of CD11b macrophages and the release of the interleukin-1β (IL-1β) and IL-18, as well as reducing the apoptosis of lung epithelial cells, thereby improving alveolar development. Notably, caspase-8 inhibition also reduced the expression of α-SMA and improved pulmonary vascular remodeling. Importantly, combination therapy increased these improvements.

CONCLUSION

Caspase-8 is an important molecular switch that regulates PCD in BPD. Selective targeted inhibition of caspase-8 reduces NLRP3 inflammasome activation, resists oxidative stress-induced lung injury, reduces the crosstalk between pyroptosis and apoptosis in lung epithelial cells, and reduces inflammatory immune cell infiltration and abnormal vascular remodeling. As such, targeting caspase-8 may be a potential strategy for the treatment of BPD.