Celastrol: A new potential therapeutic option in pulmonary hypertension associated to bronchopulmonary dysplasia - 17/02/23

Bronchopulmonary dysplasia is a common pathology of premature newborns caused by oxygen and mechanical ventilation, resulting in hypoalveolization and impaired angiogenesis [1Buczynski B.W., Maduekwe E.T., O’Reilly M.A. The role of hyperoxia in the pathogenesis of experimental BPD Semin Perinatol 2013 ;  37 : 69-78 [cross-ref]

Haga clic aquí para ir a la sección de Referencias]. It can be complicated by pulmonary hypertension (HTP-DBP) with excess mortality [2Mourani P.M., Mullen M., Abman S.H. Pulmonary hypertension in bronchopulmonary dysplasia Prog Pediatr Cardiol 2009 ;  27 : 43-48 [cross-ref]

Haga clic aquí para ir a la sección de Referencias]. Celastrol has anti-inflammatory and antioxidant properties and we addressed its potential therapeutic interest in HTP-DBP.

Different concentrations of celastrol (0.1–0.5–1mg/kg/d) were tested in a murine model of hyperoxic HTP-DBP (14days 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 (48h with 60% O₂). Inflammation and oxidant stress were also addressed.

Celastrol reduces mortality at doses of 1 and 0.5mg/kg/d compared to the Hx control group. At 1mg/kg/d, it normalizes PAAT (PA acceleration time) and reduces vascular hyperreactivity to endothelin-1 (ET-1) inversely to phenylephrine and 5-HT, with no effect on the alteration of the response to acetylcholine induced by Hx. At all doses, it decreases right heart hypertrophy and vascular remodeling (wall thickness) but has no effect on media cells proliferation (pCNA staining) observed in Hx condition. It has also no impact on alveolization and vascular density (vWF staining). 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 (qPCR and Western blotting for ET-A and B) was unchanged. In fPASMC, celastrol 0.3μM decreases the increased concentration of IL6 (ELISA) observed in Hx but has no effect on IL8 and MIF. It has no effect on the decrease of superoxide dismutase activity induced by Hx. In the murine model and fPASMC, Hx-induced oxidant stress remains mild with absence of protein carbonylation and lipid peroxidation.

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.