TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.
TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.
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DOI：
10.1038/ncomms15494
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发表时间：
2017-05-30
影响因子：
16.6
通讯作者：
Graham BB
中科院分区：
文献类型：
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作者：
Kumar R;Mickael C;Kassa B;Gebreab L;Robinson JC;Koyanagi DE;Sanders L;Barthel L;Meadows C;Fox D;Irwin D;Li M;McKeon BA;Riddle S;Dale Brown R;Morgan LE;Evans CM;Hernandez-Saavedra D;Bandeira A;Maloney JP;Bull TM;Janssen WJ;Stenmark KR;Tuder RM;Graham BB
肺动脉高压（PAH）是毛细血管前肺动脉的阻塞性疾病。血吸虫病相关的 PAH 与特发性、遗传性和自身免疫相关的病因共享改变的血管 TGF-β 信号传导；此外，TGF-β阻断可以预防临床前模型中的实验性肺动脉高压（PH）。 TGF-β 在激活水平受到调节，但 TGF-β 在这种疾病中如何被激活尚不清楚。在这里，我们发现血小板反应蛋白-1 (TSP-1) 激活 TGF-β 对于血吸虫暴露小鼠的 PH 发展是必要且充分的。接触血吸虫后，肺部 TSP-1 水平通过循环单核细胞的募集而增加，而 TSP-1 抑制或敲除骨髓可防止 TGF-β 激活并防止 PH 发展。 TSP-1 阻断还可预防第二种模型（慢性缺氧）中的 PH。最后，患有硬皮病的受试者在发生 PAH 后，TSP-1 的血浆浓度显着增加。因此，靶向 TSP-1 依赖性 TGF-β 激活可能是 TGF-β 依赖性血管疾病的一种治疗方法。 Thrombospondin-1 (TSP-1) 激活细胞外基质中潜在的 TGF-β。作者在此表明，单核细胞产生的 TSP-1 对鼠、牛和人肺中潜在的 TGF-β 的不适当激活会导致肺动脉高压，而干扰激活过程可防止疾病的发展。
Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases. Thrombospondin-1 (TSP-1) activates latent TGF-β in the extracellular matrix. Here the authors show that inappropriate activation of latent TGF-β in murine, bovine and human lung by monocyte-produced TSP-1 causes pulmonary hypertension, and that interference with the activation process prevents disease development.