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Possible Role of Lysophosphatidic Acid in Rat Model of Hypoxic Pulmonary Vascular Remodeling:

机译:溶血磷脂酸在缺氧肺血管改造大鼠模型中的可能作用:

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Pulmonary hypertension is characterized by cellular and structural changes in the vascular wall of pulmonary arteries. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling in a rat model of hypoxic pulmonary hypertension. Exposure of Wistar rats to 10% O2 for 3 weeks induced an increase in the mean serum levels of LPA, to 40.9 (log-detransformed standard deviations: 23.4–71.7) μM versus 21.6 (11.0–42.3) μM in a matched control animal group (P = 0.037). We also observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats colocalized with the secreted lysophospholipase D autotaxin (ATX). Moreover, ATX colocalized with mast cell tryptase, suggesting implication of these cells in perivascular LPA production. Hypoxic rat lungs expressed more ATX transcripts (2.4-fold) and more transcripts of proteins implicated in cell migration: β2 integrin (1.74-fold), intracellular adhesion molecule 1 (ICAM-1; 1.84-fold), and αM integrin (2.70-fold). Serum from the hypoxic group of animals had significantly higher chemoattractant properties toward rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonists. LPA also increased adhesive properties of human pulmonary artery endothelial cells as well as those of human peripheral blood mononuclear cells, via the activation of LPA receptor 1 or 3 followed by the stimulation of gene expression of ICAM-1, β?1, E-selectin, and vascular cell adhesion molecule integrins. In conclusion, chronic hypoxia increases circulating and tissue levels of LPA, which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature, both of which contribute to pulmonary vascular remodeling.
机译:肺动脉高压的特征在于肺动脉血管壁的细胞和结构变化。我们假设溶血磷脂酸(LPA),一种生物活性脂质,涉及在缺氧肺动脉高压大鼠模型中的这种血管重构中。 Wistar大鼠的暴露于10%O 2的3周诱导LPA的平均血清水平的增加,达到40.9(Log-Detralsformed标准偏差:23.4-71.7)μm与匹配的对照动物组中的21.6(11.0-42.3)μm (p = 0.037)。我们还观察到用分泌的溶血磷脂酶DAcotaxin(ATX)结合的缺氧大鼠肺部肺部血管瘤免疫组织化学染色。此外,ATX与肥大细胞胰蛋白酶分致统计化,表明这些细胞在血管外LPA生产中的含义。缺氧大鼠肺表达更多的ATX转录物(2.4倍)和更多的蛋白质转录物,含有细胞迁移的蛋白质:β2整联蛋白(1.74倍),细胞内粘附分子1(ICAM-1; 1.84倍)和αm整合蛋白(2.70-折叠)。来自缺氧的动物​​血清对大鼠原发性肺成纤维细胞具有显着更高的化疗性质,并且通过LPA受体1和3个拮抗剂可以防止细胞迁移的这种增加。通过活化LPA受体1或3,LPA还增加人肺动脉内皮细胞以及人外周血单核细胞的粘合性能,然后刺激ICAM-1,β1,e-Selectin的基因表达和血管细胞粘附分子整联。总之,慢性缺氧增加了LPA的循环和组织水平,这可能诱导肺脉管系统中单核细胞的成纤维细胞迁移和募集,这两者都有助于肺血管重塑。

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