Pulmonary hypertension (PH) associated to bronchopulmonary dysplasia (BPD-PH) is a severe cardiorespiratory disease of preterm newborns leading to an excess of mortality in infancy and no curative treatment currently exists.

We thus aimed to evaluate celastrol, an anti-inflammatory and antioxidant molecule, as a potential treatment in BPD-PH.

Celastrol was evaluated in vivo in a neonatal rat model of BPD-PH induced by hyperoxia, by assessing main hallmarks of both PH (vascular and heart remodelling, vascular reactivity, lung inflammation and oxidative stress) and BPD (alveolarisation and angiogenesis). Celastrol was also tested in vitro in human fetal pulmonary artery smooth muscle cells (HfPA-SMC) exposed to hyperoxia by assessing intracellular calcium response and endothelin-1 pathway as well as inflammation and oxidative stress.

Celastrol prevented rat mortality. In vivo, celastrol decreased PH, right heart and vascular remodelling, pulmonary arterial hyperreactivity to endothelin-1 and inflammation but had no effect on hypoalveolarisation and altered angiogenesis. In HfPA-SMC, hyperoxia increased endothelin-1-induced intracellular calcium response which was significantly inhibited by celastrol, without modifying endothelin-1 receptors expression. Finally, celastrol decreased inflammation (decrease of CD68 expression and Tissue Inhibitor of Metalloproteinases-1 secretion in rat and IL-6 secretion in HfPA-SMC) and increased heme oxygenase-1 expression in rat and HfPA-SMC.

In conclusion, since celastrol has preventive effects on major PH hallmarks in both a rat model of BPD-PH and HfPA-SMC exposed to hyperoxia, it could be a promising therapeutic option for BPD-PH.