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Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and inflammation in two murine models of acute lung injury
Intensive Care Medicine Experimental Pub Date : 2019-07-01 , DOI: 10.1186/s40635-019-0240-7
Jenny Juschten 1, 2, 3, 4 , Sarah Anne Ingelse 4, 5 , Martinus Adrianus Wilhelmus Maas 4 , Armand Roelof Johan Girbes 1, 2 , Nicole Petra Juffermans 3, 4 , Marcus Josephus Schultz 3, 6 , Pieter Roel Tuinman 1, 2
Affiliation  

In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. This study aimed to investigate whether the protease inhibitors antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an exaggerated pulmonary immune response. Lung injury was induced either by single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c mice or by combination of an intravenous injection of LPS (10 mg/kg) with subsequent injurious ventilation using high tidal volumes (12–15 ml/kg) for 4 h in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose heparin (100 U/kg). Control animals received saline. Additional controls received neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic markers of coagulation, e.g., thrombin–antithrombin complexes (TATc), and inflammation, e.g., interleukin-6. Both lung injury models resulted in a pronounced immune response within the pulmonary compartment shown by elevated levels of markers of coagulation and inflammation. The two-hit lung injury model also induced profound systemic coagulopathy and inflammation. Monotherapy with AT or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury model. Nor did combination therapy with AT and A1PI result in a decrease of coagulation or inflammatory parameters. AT markedly reduced systemic levels of TATc in the two-hit lung injury model. Systemic inflammation was not affected by the different interventions. Additional administration of heparin did not lead to macroscopic bleeding incidences. In two different murine models of acute lung injury, neither single therapy with AT or A1PI nor combination of both agents attenuates the pronounced pulmonary coagulation or inflammatory response.

中文翻译:

抗凝血酶加 α-1 蛋白酶抑制剂不影响两种急性肺损伤小鼠模型的凝血和炎症

在急性呼吸窘迫综合征 (ARDS) 中,凝血激活剂和促炎介质的不受控制的产生导致从充分的局部先天免疫反应转变为高凝状态和炎症。本研究旨在调查蛋白酶抑制剂抗凝血酶 (AT) 和 α-1 蛋白酶抑制剂 (A1PI) 是否可以减弱夸大的肺免疫反应。肺损伤是通过在 BALB/c 小鼠中单次鼻内注射脂多糖 (LPS) (5 mg/kg) 或通过静脉注射 LPS (10 mg/kg) 与随后使用高潮气量进行有害通气的组合引起的 (12 –15 ml/kg) 在 RccHan Wistar 大鼠中持续 4 小时。动物接受单独或联合的单次 AT (250 IU/kg) 或 A1PI (60 mg/kg),有或没有静脉内低剂量肝素 (100 U/kg)。对照动物接受盐水。额外的对照既不接受 LPS,也不接受通风,也不接受治疗。终点是凝血的局部和全身标志物,例如凝血酶-抗凝血酶复合物(TATc)和炎症,例如白细胞介素-6。两种肺损伤模型都导致肺隔室内出现明显的免疫反应,表现为凝血和炎症标志物水平升高。两次打击肺损伤模型还诱发了严重的全身性凝血病和炎症。在任何肺损伤模型中,AT 或 A1PI 单药治疗均未减少肺凝血病或炎症。AT 和 A1PI 的联合治疗也没有导致凝血或炎症参数的降低。AT 显着降低了两次打击肺损伤模型中 TATc 的全身水平。全身炎症不受不同干预措施的影响。额外给予肝素不会导致肉眼可见的出血发生率。在两种不同的急性肺损伤小鼠模型中,AT 或 A1PI 的单一治疗或两种药物的组合都不能减弱明显的肺凝血或炎症反应。
更新日期:2019-07-01
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