The role of inflammation in a rat model of chronic thromboembolic pulmonary hypertension induced by carrageenan
The role of inflammation in a rat model of chronic thromboembolic pulmonary hypertension induced by carrageenan
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炎症在角叉菜胶诱导的慢性血栓栓塞性肺动脉高压大鼠模型中的作用
DOI：
10.21037/atm.2020.02.86
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发表时间：
2020
影响因子：
--
通讯作者：
C. Deng
中科院分区：
文献类型：
--
作者：
Da;Yunfei Chen;Wenfeng Wang;Hongli Li;Minxia Yang;Hai;Xiaoting Lv;N. Lian;Jianming Zhao;C. Deng
研究背景慢性血栓栓塞性肺动脉高压（CTEPH）是一种由血栓和阻塞性肺动脉重构引起的危及生命的疾病，其发病率和死亡率都很高。尽管CTEPH的现代治疗在手术和药物治疗方面都取得了显著进展，但没有一种方法可以治愈这种疾病，这主要是因为我们对这种疾病的潜在发病机制的了解有限，并且缺乏可靠的CTEPH动物模型进行研究。最近，炎症已被认为是各种风险因素触发静脉血栓栓塞（VTE）形成的常见途径，我们描述了一种新型CTEPH小鼠模型，该模型重现了频繁的触发因素，并类似于CTEPH的时间过程、组织学特征和临床表现人类CTEPH，开辟了CTEPH炎症的新视野。方法8周龄雄性Sprague道利（SD）大鼠经左颈静脉连续3次注射自体血栓，以氨甲环酸（200 mg/kg.d）抑制纤溶，并注射角叉菜胶（20 mg/kg，每周1次）造成血管周围炎症，成功建立CTEPH动物模型。通过监测平均肺动脉压（mPAP）和肺组织病理学变化来评价CTEPH模型。通过RT-PCR、western blot、TUNEL、免疫组化等方法检测各亚组大鼠肺血管重构的病理变化，探讨炎症反应在肺血管重构中的作用机制。结果CTEPH组大鼠肺血管重构明显，肺血管壁面积/总面积（WA/TA）比值（85.41%±7.37% vs.76.41% ± 5.97%，P<0.05）、mPAP（25.51±1.13 vs.15.92 ±1.13 mmHg，P<0.05）明显高于对照组。单纯注射凝块与同时注射凝块和角叉菜胶的大鼠之间的平均肺动脉压（mPAP）值差异有显著性（分别为25.51± 1.13vs.29.82 ± 1.26mmHg，P<0.05）。此外，在第三次栓塞后，肺动脉中发生血栓和内膜增生。此外，反复栓塞可升高肿瘤坏死因子-α（TNF-α）、NF-κB/p65和B细胞淋巴瘤-2（BCL-2）的mRNA和蛋白水平，但以时间依赖性方式降低BAX表达。结论利用炎症反应触发静脉血栓栓塞形成，成功建立了CTEPH动物模型。炎症可能通过抑制内皮细胞凋亡在CTEPH的发病机制和进展中起关键作用。了解炎症在CTEPH中的作用不仅有助于确定最佳治疗方案，还有助于制定未来的预防策略，因为目前的抗凝治疗方案并非旨在抑制炎症。
Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition arising from the thrombus and obstructive remodeling of the pulmonary arteries, which causes a significant morbidity and mortality. Although the modern treatment in CTEPH has been significant advanced both in surgical and medical treatment, none can claim to cure the disease, largely because of our limited understanding of the underlying pathogenesis of the disease and lack of a reliable CTEPH animal model to study for. Recently, inflammation has been accepted as a common pathway through which various risk factors trigger venous thrombo-embolism (VTE) formation, we describe a novel mouse model of CTEPH which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of CTEPH in humans, to open a new horizons of inflammation in CTEPH. Methods By administering a pulmonary embolism (PE) protocol (comprising 3 sequential left jugular vein injections of autologous blood clots) to 8-week-old male Sprague Dawley (SD) rats using tranexamic acid (200 mg/kg.d) to inhibit fibrinolysis and injecting additional carrageenan (20 mg/kg, once a week) to create perivascular inflammation, we successfully generated a CTEPH animal model. By monitoring the mean pulmonary artery pressure (mPAP) and the histopathological change to evaluate the CTEPH model. By detecting the RT-PCR, western blot, TUNEL, and immunohistochemistry in the sub-groups to find the potential mechanism of inflammation may work in the pulmonary vascular remolding. Results In this study, rats with CTEPH exhibited pronounced pulmonary vascular remolding with higher vessel wall area/total area (WA/TA) ratio in comparison to the control rats (85.41%±7.37% vs. 76.41%±5.97%, P<0.05), the mPAP (25.51±1.13 vs. 15.92±1.13 mmHg, P<0.05). Significant differences in mean pulmonary artery pressure (mPAP) values were observed between rats injected solely with clots and those injected with both clots and carrageenan (25.51±1.13 vs. 29.82±1.26 mmHg, P<0.05, respectively). Furthermore, following the third embolization, thrombi and intimal hyperplasia occurred in the pulmonary artery. In addition, repeated embolization elevated mRNA and protein levels of tumor necrosis factor-α (TNF-α), NF-κB/p65, and B-cell lymphoma-2 (BCL-2), but decreased BAX expression in a time-dependent manner. Conclusions Take advantage of the inflammation to trigger VTE formation, we successfully generated a CTEPH animal model. Inflammation may play a crucial role in the pathogenesis and progression of CTEPH by inhibiting endothelial cell apoptosis. Understanding the role of inflammation in CTEPH may not only help to determine the optimal treatment options but also may aid in the development of future preventative strategies, since current anticoagulation treatment regimens are not designed to inhibit inflammation.
大型动物的慢性肺动脉栓塞模型。
DOI：
10.1007/978-1-4939-8597-5_28
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Aguero,Jaume;Hammoudi,Nadjib;Bikou,Olympia;Fish,KennethM;Zarragoikoetxea,Iratxe;Hajjar,RogerJ;Ishikawa,Kiyotake
通讯作者：
Ishikawa,Kiyotake
影响因子：
8.3
作者：
Arias-Loza, Paula-Anahi;Jung, Pius;Pelzer, Theo
通讯作者：
Pelzer, Theo