Pulmonary coagulation and fibrinolysis abnormalities that favor fibrin deposition in the lungs of mouse antibody-mediated transfusion-related acute lung injury
Pulmonary coagulation and fibrinolysis abnormalities that favor fibrin deposition in the lungs of mouse antibody-mediated transfusion-related acute lung injury
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DOI：
10.3892/mmr.2021.12239
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发表时间：
2021-06
影响因子：
3.4
通讯作者：
Yunhong Yu;Peng Jiang;P. Sun;Na Su;F. Lin
中科院分区：
文献类型：
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作者：
Yunhong Yu;Peng Jiang;P. Sun;Na Su;F. Lin
输血相关性急性肺损伤（TRALI）是一种由输血引起的危及生命的疾病。然而，对其发病机制知之甚少，也没有具体的治疗方法。实验和临床研究表明，肺泡纤维蛋白沉积在急性肺损伤中发挥病理作用。本研究调查了 TRALI 小鼠模型中是否发生肺纤维蛋白沉积以及这种沉积的可能机制。 TRALI 模型是通过在注射抗主要组织相容性复合物 I 类 (MHC-I) 抗体前 18 小时用脂多糖 (LPS) 启动雄性 Balb/c 小鼠来建立的。未治疗的小鼠和施用LPS加同种型抗体的小鼠作为对照。 TRALI诱导后2小时，收集血液和肺组织。根据肺组织组织学、炎症反应和肺泡毛细血管屏障的变化来评估疾病特征。免疫荧光染色用于检测肺纤维蛋白沉积、血小板和纤维蛋白-血小板相互作用。测量肺组织匀浆中纤溶酶原激活物抑制剂-1（PAI-1）、凝血酶-抗凝血酶复合物（TATc）、组织因子途径抑制剂（TFPI）、凝血因子活性和纤维蛋白降解产物（FDP）的水平。经LPS引发、施用抗MHC-I抗体的小鼠出现严重的肺损伤、炎症反应增加以及肺泡毛细血管屏障受损，表明TRALI模型已成功建立。小鼠模型肺部的纤维蛋白沉积、纤维蛋白-血小板相互作用和血小板积累明显促进。此外，TRALI 小鼠中 TATc、凝血因子 V (FV)、TFPI 和 PAI-1 水平升高，而 FDP 水平降低。总之，纤维蛋白溶解受损和凝血增强，这可能是由 FV 活性增强、肺部血小板积累增加和纤维蛋白-血小板相互作用增强引起的，并导致 TRALI 小鼠的肺纤维蛋白沉积。结果为抗体介导的 TRALI 的凝血或纤溶途径异常提供了治疗依据。
Transfusion-related acute lung injury (TRALI) is a life-threatening disease caused by blood transfusion. However, its pathogenesis is poorly understood and specific therapies are not available. Experimental and clinical studies have indicated that alveolar fibrin deposition serves a pathological role in acute lung injuries. The present study investigated whether pulmonary fibrin deposition occurs in a TRALI mouse model and the possible mechanisms underlying this deposition. The TRALI model was established by priming male Balb/c mice with lipopolysaccharide (LPS) 18 h prior to injection of an anti-major histocompatibility complex class I (MHC-I) antibody. Untreated mice and mice administered LPS plus isotype antibody served as controls. At 2 h after TRALI induction, blood and lung tissue were collected. Disease characteristics were assessed based on lung tissue histology, inflammatory responses and alterations in the alveolar-capillary barrier. Immunofluorescence staining was used to detect pulmonary fibrin deposition, platelets and fibrin-platelet interactions. Levels of plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TATc), tissue factor pathway inhibitor (TFPI), coagulation factor activity and fibrin degradation product (FDP) in lung tissue homogenates were measured. Severe lung injury, increased inflammatory responses and a damaged alveolar-capillary barrier in the LPS-primed, anti-MHC-I antibody-administered mice indicated that the TRALI model was successfully established. Fibrin deposition, fibrin-platelet interactions and platelets accumulation in the lungs of mouse models were clearly promoted. Additionally, levels of TATc, coagulation factor V (FV), TFPI and PAI-1 were elevated, whereas FDP level was decreased in TRALI mice. In conclusion, both impaired fibrinolysis and enhanced coagulation, which might be induced by boosted FV activity, increased pulmonary platelets accumulation and enhanced fibrin-platelet interactions and contributed to pulmonary fibrin deposition in TRALI mice. The results provided a therapeutic rationale to target abnormalities in either coagulation or fibrinolysis pathways for antibody-mediated TRALI.