PDF(Pubmed)
Abstract：
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arterial pressure, inflammation, and neointimal remodeling of pulmonary arterioles. Serum levels of interleukin (IL)-1β and IL-18 are elevated in PAH patients and may enhance proinflammatory neointimal remodeling. NLRP3 inflammasome activation induces cleavage of the cytokines IL-1β and IL-18, required for their secretion. Pirfenidone (PFD), an antifibrotic and anti-inflammatory drug, has been suggested to inhibit NLRP3 inflammasome activation. We hypothesized that PFD delays the progression of PAH by suppressing NLRP3 inflammasome activation. We assessed the effects of PFD treatment in a rat model for neointimal PAH induced by monocrotaline and aortocaval shunt using echocardiographic, hemodynamic, and vascular remodeling parameters. We measured inflammasome activation by NLRP3 immunostaining, Western blots for caspase-1, IL-1β, and IL-18 cleavage, and macrophage IL-1β secretion. PFD treatment ameliorated pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular remodeling in PAH rats. In PAH rats, immunostaining of NLRP3 in pulmonary arterioles and caspase-1, IL-1β, and IL-18 cleavage in lung homogenates were increased compared to controls, reflecting NLRP3 inflammasome activation in vivo. PFD decreased IL-1β and IL-18 cleavage, as well as macrophage IL-1β secretion in vitro. Our studies show that PFD ameliorates pulmonary hemodynamics and vascular remodeling in experimental PAH. Although PFD did not affect all NLRP3 inflammasome parameters, it decreased IL-1β and IL-18 cleavage, the products of NLRP3 inflammasome activation that are key to its downstream effects. Our findings thus suggest a therapeutic benefit of PFD in PAH via suppression of NLRP3 inflammasome activation.
摘要：
肺动脉高压（PAH）是一种致命的疾病，其特征是肺动脉压升高，炎症,和肺小动脉的新内膜重塑。PAH患者的血清白细胞介素（IL）-1β和IL-18水平升高，并可能增强促炎性新内膜重塑。NLRP3炎性体活化诱导分泌所需的细胞因子IL-1β和IL-18的裂解。吡非尼酮(PFD),抗纤维化和抗炎药，有人建议抑制NLRP3炎性体的激活。我们假设PFD通过抑制NLRP3炎性体激活来延迟PAH的进展。我们使用超声心动图评估了PFD治疗对野百合碱和主动脉腔分流术诱导的新内膜PAH的大鼠模型的影响，血液动力学,和血管重塑参数。我们通过NLRP3免疫染色测量了炎症体的激活，caspase-1，IL-1β的蛋白质印迹，和IL-18裂解，和巨噬细胞IL-1β分泌。PFD治疗改善肺动脉压，肺血管阻力,PAH大鼠肺血管重构。在PAH大鼠中,肺小动脉中NLRP3的免疫染色和caspase-1，IL-1β，与对照组相比，肺匀浆中的IL-18裂解增加，反映体内NLRP3炎性体激活。PFD降低IL-1β和IL-18裂解，以及巨噬细胞IL-1β的体外分泌。我们的研究表明，PFD可以改善实验性PAH中的肺血流动力学和血管重塑。尽管PFD并未影响所有NLRP3炎性体参数，它减少了IL-1β和IL-18的切割，NLRP3炎性体激活的产物是其下游效应的关键。因此，我们的发现表明PFD通过抑制NLRP3炎性体激活在PAH中的治疗益处。
