Pyroptosis is a pro-inflammatory form of programmed cell death, whose genesis directly depended on caspase-1 activation. Pulmonary hypertension (PH) is a disease characterized, in part, by vascular fibrosis. Up to now, there is no report on the relationship between pyroptosis and vascular fibrosis in PH. Here, we confirmed that pyroptosis had occurred in the media of pulmonary arteries in two PH rat models and hypoxic human pulmonary arterial smooth muscle cells (hPASMCs). Caspase-1 inhibition attenuated the pathogenesis of PH, as assessed by vascular remodeling, right ventricular systolic pressure, right ventricle hypertrophy and hemodynamic parameters of pulmonary vasculature. Moreover, caspase-1 inhibition suppressed pulmonary vascular fibrosis as demonstrated by Masson staining, as well as immunohistochemistry and Western blot analysis of fibrillar collagen. In addition, Programmed death-ligand 1 (PD-L1) was markedly increased in PH, which was regulated by the transcription factor STAT1. Furthermore, PD-L1 knockdown in hPASMCs repressed the onset of hypoxia-induced pyroptosis and fibrosis. Overall, these data identify a critical STAT1-dependent posttranscriptional modification that promotes PD-L1 expression in the pyroptosis of PASMCs to modulate pulmonary vascular fibrosis and accelerate the progression of PH.

中文翻译：

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编程的死亡配体1触发了肺动脉高压中的PASMCs凋亡和肺血管纤维化。

细胞凋亡是程序性细胞死亡的促炎形式，其起源直接取决于caspase-1的激活。肺动脉高压（PH）是一种以血管纤维化为特征的疾病。到目前为止，尚无关于PH的细胞凋亡与血管纤维化之间关系的报道。在这里，我们证实了在两个PH大鼠模型和缺氧性人肺动脉平滑肌细胞（hPASMCs）的肺动脉介质中发生了热凋亡。通过血管重塑，右心室收缩压，右心室肥大和肺血管系统的血流动力学参数评估，Caspase-1抑制作用减弱了PH的发病机理。此外，如Masson染色所示，caspase-1抑制可抑制肺血管纤维化，以及原纤维胶原蛋白的免疫组织化学和蛋白质印迹分析。此外，程序性死亡配体1（PD-L1）的PH明显升高，这受转录因子STAT1的调节。此外，hPASMCs中的PD-L1敲低抑制了低氧引起的焦磷酸化和纤维化的发生。总体而言，这些数据确定了关键的STAT1依赖性转录后修饰，该修饰可促进PASMC的热凋亡中PD-L1的表达，从而调节肺血管纤维化并加速PH的发展。