Celastrol: A new potential therapeutic option in pulmonary hypertension associated with bronchopulmonary dysplasia

Introduction

Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxygen and mechanical ventilation, resulting in hypoalveolarization and impaired angiogenesis. It can be complicated by pulmonary hypertension (PH-BPD) with excess mortality. Celastrol has anti-inflammatory and antioxidant properties.

Objective

We addressed potential therapeutic interest of celastrol in PH-BPD.

Methods

Different concentrations of celastrol (0,1–0,5–1 mg/kg/d) were tested in a murine model of hyperoxic PH-BPD (14 days with 90% O₂–Hx). We evaluated hemodynamic parameters with echocardiography, lung remodeling with histological methods and pulmonary arterial (PA) reactivity 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 Hx conditions (48 h with 60% O₂). Inflammation and oxidant stress were also addressed.

Results/Expected results

Celastrol reduces mortality at doses of 1 and 0,5 mg/kg/d compared to Hx control. At 1 mg/kg/d, it normalizes PA acceleration time and reduces vascular hyperreactivity to ET-1 inversely to phenylephrine and 5-HT, with no effect on the altered response to acetylcholine induced by Hx. At all doses, it decreases right heart hypertrophy and vascular remodeling but has no effect on media cells proliferation observed in Hx condition. It has also no impact on alveolarization and vascular density. Although celastrol (0.1 and 0.3 μM) decreases the increased Ca₂+i response to ET-1 in Hx in fPASMC, expression of ET-1 receptors was unchanged. In fPASMC, celastrol 0.3 μM decreases the increased concentration of IL6 observed in Hx but has no effect on IL8 and MIF. In both models, Hx-induced oxidant stress remains mild with absence of protein carbonylation and lipid peroxidation and celastrol at 1 mg/kg/d increases heme oxygenase 1 expression.

Conclusion/Perspectives

Celastrol has a preventive dose-dependent effect on major hallmarks of PH induced by Hx and could be considered as a new potential therapeutic option for PH-BPD.