Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury.
Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury.
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DOI：
10.1160/th17-05-0347
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发表时间：
2017-11
影响因子：
6.7
通讯作者：
Artigas A
中科院分区：
文献类型：
--
作者：
Chimenti L;Camprubí-Rimblas M;Guillamat-Prats R;Gomez MN;Tijero J;Blanch L;Artigas A
目的肺泡巨噬细胞在急性呼吸窘迫综合征（ARDS）的发生、发展和转归中起重要作用，调节肺内炎症反应和凝血级联反应。 抗凝剂可能有助于ARDS的治疗。本研究探讨了雾化肝素对急性肺损伤（ALI）动物模型肺泡巨噬细胞限制肺凝血和炎症反应的作用。 方法将大鼠随机分为4个实验组。 LPS/Hep组于伤后4 h、8h雾化吸入肝素，Hep/LPS/Hep组于伤前30 min、伤后4 h、8h雾化吸入肝素，LPS/Sal组于伤后4 h、8h雾化吸入生理盐水。对照组仅给予生理盐水。在LPS滴注后24小时将动物放血。分析肺组织、支气管肺泡灌洗液（BALF）和从BALF中分离的肺泡巨噬细胞。 结果LPS可增加支气管肺泡灌洗液中蛋白浓度、水肿和中性粒细胞，并增加肺组织和肺泡巨噬细胞中促凝血和促炎症介质。 在肺组织中，雾化肝素通过减少促凝剂（组织因子、凝血酶-抗凝血酶复合物、纤维蛋白降解产物）和促炎剂（白细胞介素6、肿瘤坏死因子α）途径来减轻ALI。在肺泡巨噬细胞中，雾化肝素降低了促凝血基因和转化生长因子β（Smad 2，Smad 3）和核因子κ B（p-选择素，CCL-2）效应子的表达。预处理导致更明显的衰减。 结论雾化肝素可减轻肺凝血功能障碍和炎症反应，而不引起全身出血，其机制可能与调节肺泡巨噬细胞有关。
Objective Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI). Methods Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed. Results LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin–anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation. Conclusion Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages.