Bronchopulmonary dysplasia is a common disease of premature newborns caused by oxidative stress and mechanical ventilation in these immature lungs, resulting in hypoalveolization and impaired angiogenesis. It can be complicated by pulmonary hypertension (HTP-DBP), and then right heart failure associated with excess mortality at 2 years of age. Celastrol has anti-inflammatory and antioxidant properties. Furthermore, in a mouse model of systemic hypertension, it decreases systemic blood pressure and inhibits vascular remodeling and myocardial hypertrophy by reducing inflammation and oxidative stress in vascular smooth muscle cells (VSMCs). It is therefore a molecule of choice for the study of a preventive treatment of HTP-DBP.

We studied the influence of celastrol in a mouse model of hyperoxic HTP-DBP by evaluating survival, HTP with measurement of pulmonary artery acceleration time (PAAT), right vascular remodeling, alveolization as well pulmonary vascular density, reactivity and remodeling. We also evaluated calcium response of human fetal pulmonary VSMCs.

Celastrol reduced mortality at doses of 1 and 0.5mg/kg/d. At 1mg/kg/d, it normalized PAAT and reduced vascular hyperreactivity with no effect on the alteration of the response to acetylcholine induced by hyperoxia. It decreased cardiac and pulmonary vascular remodeling at all concentrations tested but had no effect on alveolization and pulmonary vascular density. Finally, it decreased also calcium hyperreactivity of human fetal pulmonary VSMCs exposed to hyperoxia.

Celastrol had a preventive effect on HTP but not on DBP itself. However, mechanisms involved remain unknown.