1 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)1148, DHU FIRE (Département Hospitalo-Universitaire Fibrosis, Inflammation, REmodeling in cardiovascular, respiratory and renal diseases), Paris, France.
Am J Respir Cell Mol Biol. 2014 Oct;51(4):536-49. doi: 10.1165/rcmb.2013-0103OC.
Several studies report that high-density lipoproteins (HDLs) can carry α1-antitrypsin (AAT; an elastase inhibitor). We aimed to determine whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75 mg apolipoprotein A1/kg), HDL-AAT (75 mg apolipoprotein A1-3.75 mg AAT/kg), or AAT alone (3.75 mg/kg) at 2, 24, 48, and 72 hours. We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length, 22.9 ± 2.8 μm versus 30.7 ± 4.5 μm; P < 0.001), whereas injection of HDL or AAT alone only showed a moderate, nonsignificant protective effect (28.2 ± 4.2 μm versus 30.7 ± 5 μm [P = 0.23] and 27.3 ± 5.66 μm versus 30.71 ± 4.96 μm [P = 0.18], respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (P = 0.006 and P = 0.048, respectively). This protective effect was associated (at 6, 24, and 72 h) with: (1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid; (2) decreased concentrations of IL-6, monocyte chemoattractant protein-1, and TNF-α in both bronchoalveolar lavage fluid and plasma; (3) a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-9 activities; and (4) a reduction in the degradation of fibronectin, a marker of tissue damage. In addition, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Intravenous HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency.
几项研究报告称，高密度脂蛋白（HDL）可以携带α1-抗胰蛋白酶（AAT；弹性蛋白酶抑制剂）。我们旨在确定注射外源性富含或不富含 AAT 的 HDL 是否可能对肺气肿具有保护作用。在气管内给予生理盐水或弹性酶后，小鼠随机经静脉给予生理盐水、人血浆 HDL（75 mg 载脂蛋白 A1/kg）、HDL-AAT（75 mg 载脂蛋白 A1-3.75 mg AAT/kg）或单独 AAT（3.75 mg/kg），在 2、24、48 和 72 小时时进行处理。我们已经表明，HDL-AAT 在 3 周时达到肺部并预防了 59.3%的肺气肿发展（肺泡平均弦长，22.9 ± 2.8 μm 对 30.7 ± 4.5 μm；P < 0.001），而单独注射 HDL 或 AAT 仅显示出适度的、无统计学意义的保护作用（28.2 ± 4.2 μm 对 30.7 ± 5 μm [P = 0.23] 和 27.3 ± 5.66 μm 对 30.71 ± 4.96 μm [P = 0.18]）。实际上，HDL-AAT 的保护作用明显高于 HDL 或 AAT（P = 0.006 和 P = 0.048）。这种保护作用与以下因素相关（在 6、24 和 72 小时时）：（1）支气管肺泡灌洗液中中性粒细胞和巨噬细胞数量减少；（2）支气管肺泡灌洗液和血浆中白细胞介素-6、单核细胞趋化蛋白-1 和肿瘤坏死因子-α的浓度降低；（3）基质金属蛋白酶-2 和基质金属蛋白酶-9 活性降低；（4）纤维连接蛋白降解减少，纤维连接蛋白是组织损伤的标志物。此外，HDL-AAT 减轻了急性香烟烟雾引起的炎症反应。静脉内 HDL-AAT 治疗对弹性酶诱导的肺气肿的保护作用优于单独 AAT，可能是治疗 AAT 缺乏症相关肺气肿的重要进展。
