Farkas Daniela, Alhussaini Aysar A, Kraskauskas Donatas, Kraskauskiene Vita, Cool Carlyne D, Nicolls Mark R, Natarajan Ramesh, Farkas Laszlo
1 Victoria Johnson Center for Lung Research, Department of Internal Medicine, Division of Pulmonary Disease and Critical Care, Virginia Commonwealth University, Richmond, Virginia.
Am J Respir Cell Mol Biol. 2014 Sep;51(3):413-25. doi: 10.1165/rcmb.2013-0355OC.
NF-κB and IL-6, a NF-κB downstream mediator, play a central role in the inflammatory response of tissues. We aimed to determine the role of the classical NF-κB pathway in severe pulmonary arterial hypertension (PAH) induced by SU5416 and chronic hypoxia (SuHx) in rats. Tissue samples from patients with idiopathic PAH (iPAH) and control subjects were investigated. SuHx rats were treated from Days 1 to 3, 1 to 21, and 29 to 42 with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and/or from Days 1 to 21 with anti-IL-6 antibody. Nuclear staining for NF-κB, an indicator of the activation of the classical NF-κB pathway, was detected in pulmonary arterial lesions of patients with iPAH and SuHx rats. NF-κB inhibition with PDTC prevented and reduced pulmonary arterial obliteration without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. PDTC treatment prevented or reduced apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration. IL-6 inhibition had only a partial effect on apoptosis and obliteration. Pulmonary arterial media wall thickness was not affected by any of these treatments. Preventive and therapeutic PDTC treatment promoted immune regulation by increasing the number of perivascular CD4(+) T cells, in particular regulatory T cells (early treatment), and by reducing the number of perivascular CD8(+) T lymphocytes and CD45RA(+) B lymphocytes. Therapeutic PDTC treatment further preserved right ventricular function in SuHx animals. Inhibition of NF-κB may represent a therapeutic option for pulmonary arterial obliteration via reduced vessel wall cell apoptosis and improved regulation of the immune system.
核因子-κB（NF-κB）以及NF-κB下游介质白细胞介素-6（IL-6）在组织炎症反应中起核心作用。我们旨在确定经典NF-κB信号通路在大鼠由SU5416和慢性低氧诱导的重度肺动脉高压（PAH）中的作用。对特发性PAH（iPAH）患者和对照受试者的组织样本进行了研究。从第1天至第3天、第1天至第21天以及第29天至第42天，用NF-κB抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）对慢性低氧大鼠进行治疗，和/或从第1天至第21天用抗IL-6抗体进行治疗。在iPAH患者和慢性低氧大鼠的肺动脉病变中检测到NF-κB的核染色，这是经典NF-κB信号通路激活的指标。用PDTC抑制NF-κB可预防和减轻肺动脉闭塞，但不减少肌化。然而，在接受PDTC治疗的慢性低氧动物中，肺组织中升高的IL-6水平并未降低。PDTC治疗可预防或减少肺动脉壁细胞凋亡和肺动脉闭塞。抑制IL-6对细胞凋亡和闭塞仅有部分作用。这些治疗均未影响肺动脉中膜壁厚度。预防性和治疗性PDTC治疗通过增加血管周围CD4(+) T细胞数量，特别是调节性T细胞数量（早期治疗），并减少血管周围CD8(+) T淋巴细胞和CD45RA(+) B淋巴细胞数量，促进免疫调节。治疗性PDTC治疗进一步保留了慢性低氧动物的右心室功能。抑制NF-κB可能是通过减少血管壁细胞凋亡和改善免疫系统调节来治疗肺动脉闭塞的一种选择。
