Celastrol has beneficial effects on pulmonary hypertension associated with bronchopulmonary dysplasia: Preclinical study outcomes

Abstract

Pulmonary hypertension associated with 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. Inflammation and oxidative stress are the common pathways that lead to BPD-PH. Therefore, we aimed to evaluate celastrol, a molecule with anti-inflammatory and antioxidant properties, as a promising preventive treatment in BPD-PH. In a model of neonatal rats exposed to hyperoxia, we demonstrated that mortality was prevented in animals treated with celastrol. Moreover, in vivo, celastrol decreased pulmonary hypertension, right ventricular hypertrophy, vascular remodeling, pulmonary arterial hyperreactivity to endothelin-1 and inflammation but had no effect on hypoalveolarization and altered angiogenesis. In vitro experiments carried out on human fetal pulmonary artery smooth muscle cells (HfPA-SMC) exposed to hyperoxia showed that endothelin-1-induced intracellular calcium response was increased and celastrol significantly inhibited this effect, without modifying endothelin-1 receptors expression. Regarding inflammation, celastrol decreased both CD68 staining in lung and secretion of the pro-inflammatory cytokine Tissue Inhibitor of Metalloproteinases-1 in intrapulmonary arteries from neonatal rats. IL-6 secretion was also decreased by celastrol in HfPA-SMC. Finally, hyperoxia increased heme oxygenase-1 (HO-1) expression and celastrol induced an overexpression of HO-1 in both neonatal rat lung and human cells. These results suggest that celastrol has a preventive effect on major hallmarks of PH in both a rat hyperoxic model of BPD-PH and HfPA-SMC exposed to hyperoxia via modulation of macrophage inflammatory signaling and HfPA-SMC calcium cycling. Celastrol could therefore be considered as a promising preventive treatment in BPD-PH.