Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxidative stress and mechanical ventilation, resulting in hypoalveolization and impaired angiogenesis. It can be complicated by pulmonary hypertension (HTP-DBP) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties and we addressed its potential therapeutic interest in HTP-DBP.

The aim of the study was to evaluate celastrol's effects as a preventive treatment of HTP-DBP on murine and human models.

Different concentrations of celastrol (0.1, 0.5 and 1mg/kg/d) were used in a murine model of hyperoxic HTP-DBP (14 days with 90% O2) and we evaluated hemodynamic parameters with echocardiography and lung remodeling with histological methods. Pulmonary arterial (PA) reactivity was addressed with myograph. Cytoplasmic calcium (Ca2+i) response to endothelin-1 (ET-1) was evaluated in human fetal PA smooth muscle cells (fPASMC) with spectrophotometry in normoxic (21% O2) and hyperoxic conditions (48h with 60% O2). Inflammation was addressed with IL6 ELISA assay in fPASMC.

Celastrol reduces mortality at doses of 1 and 0.5mg/kg/d compared to the hyperoxic control group. At 1mg/kg/d, it normalizes PA acceleration time (PAAT) (P<0.001) and reduces vascular hyperreactivity to phenylephrine and ET-1 (P<0.001 and < 0.05, respectively) with no effect on the alteration of the response to acetylcholine induced by hyperoxia. At doses of 0.1, 0.5 and 1mg/kg/d, it decreases right heart hypertrophy and vascular remodeling (wall thickness) but has no effect on alveolization and vascular density (vWF staining). Finally, although celastrol (0.1 and 0.3μM) decreases the increased Ca2+i response to ET-1 in hyperoxia in fPASMC, expression of ET-1 receptors (Western blotting and qPCR for ET-A and ET-B) was unchanged. An increased concentration of IL6 was also observed in fPASMC in hyperoxia and was decreased by celastrol 0.3μM.

Celastrol has a preventive dose-dependent effect on some hallmarks of HTP induced by hyperoxia and could thus be considered as an interesting new potential therapeutic option for HTP-DBP.