Pilard Claire-Marie, Cardouat Guillaume, Gauthereau Isabel, Gassiat Laure, Dubois Mathilde, Robillard Paul, Sauvestre Fanny, Pelluard Fanny, Berenguer Sophie, Sarreau Melie, Claverol Stéphane, Tokarski Caroline, Sentilhes Loïc, Coatleven Frederic, Vincienne Marie, Marthan Roger, Dumas-de-la-Roque Eric, Berger Patrick, Friedberg Mark K, Renesme Laurent, Freund-Michel Véronique, Guibert Christelle
Plateforme Technologique d'Innovation Biomédicale, Pessac F-33600, France; INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, University of Bordeaux, Pessac F-33600, France; Neonatology Department, Bordeaux University Hospital, Bordeaux F-33000, France.
Plateforme Technologique d'Innovation Biomédicale, Pessac F-33600, France; INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, University of Bordeaux, Pessac F-33600, France.
Biomed Pharmacother. 2025 Mar;184:117881. doi: 10.1016/j.biopha.2025.117881. Epub 2025 Feb 1.
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.
支气管肺发育不良相关的肺动脉高压（BPD-PH）是一种早产新生儿的严重心肺疾病，会导致婴儿期死亡率过高，目前尚无治愈方法。炎症和氧化应激是导致BPD-PH的常见途径。因此，我们旨在评估具有抗炎和抗氧化特性的雷公藤红素，作为BPD-PH中有前景的预防性治疗药物。在新生大鼠暴露于高氧的模型中，我们证明用雷公藤红素治疗的动物死亡率降低。此外，在体内，雷公藤红素降低了肺动脉高压、右心室肥大、血管重塑、肺动脉对内皮素-1的高反应性和炎症，但对肺泡化不足和血管生成改变没有影响。在暴露于高氧的人胎儿肺动脉平滑肌细胞（HfPA-SMC）上进行的体外实验表明，内皮素-1诱导的细胞内钙反应增加，雷公藤红素显著抑制了这种作用，而不改变内皮素-1受体的表达。关于炎症，雷公藤红素降低了新生大鼠肺中的CD68染色以及肺内动脉中促炎细胞因子金属蛋白酶组织抑制剂-1的分泌。在HfPA-SMC中，雷公藤红素也降低了IL-6的分泌。最后，高氧增加了血红素加氧酶-1（HO-1）的表达，雷公藤红素在新生大鼠肺和人细胞中均诱导了HO-1的过表达。这些结果表明，雷公藤红素通过调节巨噬细胞炎症信号和HfPA-SMC钙循环，对BPD-PH大鼠高氧模型和暴露于高氧的HfPA-SMC中的肺动脉高压主要特征具有预防作用。因此，雷公藤红素可被认为是BPD-PH中有前景的预防性治疗药物。
