Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Building RC2, 9th floor, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, USA.
Nat Commun. 2017 May 30;8:15494. doi: 10.1038/ncomms15494.
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.
肺动脉高压（PAH）是一种前毛细血管性肺动脉阻塞性疾病。与特发性、遗传性和自身免疫性相关病因一样，血吸虫病相关的 PAH 存在血管转化生长因子-β（TGF-β）信号改变；此外，TGF-β 阻断可预防临床前模型中的实验性肺动脉高压（PH）。TGF-β在激活水平上受到调节，但在这种疾病中 TGF-β 如何被激活尚不清楚。在这里，我们显示血栓素-1（TSP-1）对 TGF-β的激活对于暴露于血吸虫的小鼠 PH 的发展是必需且充分的。在接触血吸虫后，通过募集循环单核细胞，肺中的 TSP-1 水平增加，而 TSP-1 抑制或敲除骨髓可防止 TGF-β的激活并预防 PH 的发展。TSP-1 阻断也可预防慢性低氧的 PH。最后，在发生 PAH 后，硬皮病患者的血浆 TSP-1 浓度显著升高。因此，靶向依赖于 TSP-1 的 TGF-β激活可能是 TGF-β依赖性血管疾病的一种治疗方法。
