1 Department of Respiratory Medicine.
2 Department of Pharmacology and.
Am J Respir Crit Care Med. 2018 Jul 15;198(2):232-244. doi: 10.1164/rccm.201709-1783OC.
Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains elusive.
To determine the role of NOSs in BM cells in PH.
Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS), iNOS (inducible NOS), eNOS (endothelial NOS), and n/i/eNOSs mice.
In the patients, there was a significant correlation between higher pulmonary artery systolic pressure and lower nitrite plus nitrate levels in the BAL fluid. In the mice, hypoxia-induced PH deteriorated significantly in the n/i/eNOSs genotype and, to a lesser extent, in the eNOS genotype as compared with the WT genotype. In the n/i/eNOSs genotype exposed to hypoxia, the number of circulating BM-derived vascular smooth muscle progenitor cells was significantly larger, and transplantation of green fluorescent protein-transgenic BM cells revealed the contribution of BM cells to pulmonary vascular remodeling. Importantly, n/i/eNOSs-BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs genotype. A total of 69 and 49 mRNAs related to immunity and inflammation, respectively, were significantly upregulated in the lungs of WT genotype mice transplanted with n/i/eNOSs-BM compared with those with WT-BM, suggesting the involvement of immune and inflammatory mechanisms in the exacerbation of hypoxia-induced PH caused by n/i/eNOSs-BM transplantation.
These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.
一氧化氮（NO）由NOS（一氧化氮合酶）合成，在肺动脉高压（PH）的发展中起作用。然而，NO/NOS 在 PH 中的骨髓（BM）细胞中的作用仍不清楚。
确定 NOS 在 PH 中的 BM 细胞中的作用。
在 36 名特发性肺纤维化患者和野生型（WT）、nNOS（神经元 NOS）、iNOS（诱导型 NOS）、eNOS（内皮 NOS）和 n/i/eNOSs 小鼠上进行了实验。
在患者中，肺动脉收缩压较高与 BAL 液中硝酸盐加硝酸盐水平较低之间存在显著相关性。在小鼠中，与 WT 基因型相比，缺氧诱导的 PH 在 n/i/eNOSs 基因型中明显恶化，在 eNOS 基因型中恶化程度较轻。在暴露于缺氧的 n/i/eNOSs 基因型中，循环 BM 来源的血管平滑肌祖细胞数量明显增加，并且绿色荧光蛋白转导的 BM 细胞移植显示 BM 细胞对肺血管重塑的贡献。重要的是，n/i/eNOSs-BM 移植在 WT 基因型中显著加重了缺氧诱导的 PH，而 WT-BM 移植在 n/i/eNOSs 基因型中显著改善了缺氧诱导的 PH。与 WT-BM 移植相比，WT 基因型小鼠移植 n/i/eNOSs-BM 后，共有 69 种和 49 种与免疫和炎症相关的 mRNA 分别显著上调，表明免疫和炎症机制参与了 n/i/eNOSs-BM 移植引起的缺氧诱导的 PH 加重。
这些结果表明骨髓髓系 n/i/eNOSs 在 PH 的发病机制中发挥重要的保护作用。
