Effect of Celastrol on pulmonary hypertension associated to bronchopulmonary dysplasia: preclinical study outcomes

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 <italic>in vivo</italic> 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 <italic>in vitro</italic> 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. <italic>In vivo</italic>, 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.