Research Center, Montreal Heart Institute, 5000 Bélanger est, Montreal, QC H1T 1C8, Canada.
Prometic Biosciences Inc., 440 Boulevard Armand-Frappier, QC, H7V 4B4, Canada.
Cardiovasc Res. 2020 Jan 1;116(1):171-182. doi: 10.1093/cvr/cvz034.
Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model.
HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation.
PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-β, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.
射血分数降低的心力衰竭（HFrEF）导致成纤维细胞增殖和纤维化，导致肺重塑，从而导致肺动脉高压（PH）和右心室（RV）功能障碍的限制性肺病综合征。PBI-4050 是一种首创的抗纤维化、抗炎和抗增殖化合物。本研究评估了 PBI-4050 在 HFrEF 模型中对 PH 的治疗作用。
在大鼠心肌梗死（MI）后诱导 HFrEF。2 周后，假手术组和 MI 组接受 PBI-4050（通过灌胃 200mg/kg/天）或生理盐水治疗 3 周。根据梗死面积将动物分为大（≥30%左心室）或中 MI（<30%）。大 MI 导致 PH 和 RVH，并伴有限制性肺病综合征。PBI-4050 不会对左心室（LV）功能产生不利影响，但可显著降低 PH 和 RVH，并改善 RV 功能障碍。PBI-4050 减少了肺重塑，改善了呼吸顺应性，降低了肺纤维化、肺泡壁细胞增殖和α-平滑肌肌动蛋白表达。HFpEF 肺中内皮素-1（ET-1）、转化生长因子β（TGF-β）、白细胞介素-6（IL-6）和金属蛋白酶组织抑制剂-1 的表达增加，经 PBI-4050 治疗后减少。PBI-4050 显著降低了分离的人肺成纤维细胞（HLFs）向肌成纤维细胞促纤维化表型的激活。HFpEF 肺和激活的 HLFs 中的脂肪酸受体 GPR84 增加，并用 PBI-4050 减少。GPR84 激动剂激活 HLFs 的纤维化，最终 PBI-4050 降低 ERK1/2 磷酸化。
PBI-4050 通过减少肺纤维化和重塑来降低 HFrEF 中的 PH 和 RVH。这种新型药物可减少相关的限制性肺病综合征并恢复 RV 功能。一种促成机制涉及通过拮抗 GPR84 和减少 ERK1/2 磷酸化来减少由 IL-6、TGF-β 和 ET-1 引起的肺成纤维细胞的激活。PBI-4050 是一种针对 II 型 PH 中肺重塑的新型有前途的治疗方法。
Zotero 插件