Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.
Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease.
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DOI：
10.1002/art.30255
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发表时间：
2011-05
影响因子：
--
通讯作者：
Silver, Richard M.
中科院分区：
文献类型：
--
作者：
Bogatkevich, Galina S.;Ludwicka-Bradley, Anna;Nietert, Paul J.;Akter, Tanjina;van Ryn, Joanne;Silver, Richard M.
凝血级联反应的激活导致凝血酶的产生，这在包括系统性硬化症相关的各种形式的肺损伤中已有大量文献记载。我们先前证明直接凝血酶抑制剂（DTI）达比加群可抑制凝血酶诱导的肺成纤维细胞的促纤维化信号传导。本研究测试了达比加群是否能减轻间质性肺病小鼠模型中的肺损伤。
通过单次气管内滴注博来霉素在6 - 8周龄的雌性C57BL/6小鼠中诱导肺损伤。从博来霉素滴注后的第1天（早期治疗，抗炎作用）或第8天（晚期治疗，抗纤维化作用）开始，给予达比加群酯添加在食物中。在博来霉素滴注后2周和3周，对小鼠实施安乐死；对肺组织、支气管肺泡灌洗液（BALF）和血浆进行研究。
达比加群酯的早期和晚期治疗均减轻了博来霉素诱导的肺纤维化的发展。达比加群酯显著降低了BALF中的凝血酶活性以及转化生长因子 - β1（TGF - β1）和血小板源性生长因子 - AA（PDGF - AA）的水平，同时减少了炎症细胞和蛋白质浓度。在达比加群酯治疗的小鼠中，肺部的组织学炎症和纤维化显著减轻。此外，达比加群酯降低了博来霉素诱导的肺纤维化小鼠中的胶原蛋白、结缔组织生长因子（CTGF）和α - 平滑肌肌动蛋白（α - SMA）的表达，而对这些蛋白质的基础水平没有影响。
使用口服直接凝血酶抑制剂达比加群酯抑制凝血酶在博来霉素诱导的肺纤维化模型中具有显著的抗炎和抗纤维化作用。我们的数据提供了关于达比加群酯作为一种治疗间质性肺病的新治疗方法的可行性和有效性的临床前信息。
Activation of the coagulation cascade leading to generation of thrombin has been extensively documented in various forms of lung injury including that associated with systemic sclerosis. We previously demonstrated that direct thrombin inhibitor (DTI) dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study tested whether dabigatran attenuates lung injury in a murine model of interstitial lung disease. Lung injury was induced in 6–8 week old female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 (early treatment, anti-inflammatory effect) or on day 8 (late treatment, anti-fibrotic effect) following bleomycin instillation. Two and three weeks after bleomycin instillation mice were euthanized; lung tissue, bronchoalveolar lavage fluid (BALF), and plasma were investigated. Both early and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of TGF-β1 and PDGF-AA in BALF simultaneously decreasing inflammatory cells and protein concentrations. Histological lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, CTGF, and α-SMA expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins. Inhibition of thrombin using the oral DTI dabigatran etexilate has marked anti-inflammatory and anti-fibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung diseases.
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DOI：
10.1111/j.1600-6143.2009.02924.x
发表时间：
2010-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Favreau F;Thuillier R;Cau J;Milin S;Manguy E;Mauco G;Zhu X;Lerman LO;Hauet T
通讯作者：
Hauet T
影响因子：
9.6
作者：
Kubo, H;Nakayama, K;Sasaki, H
通讯作者：
Sasaki, H
影响因子：
6
作者：
Howell, DCJ;Johns, RH;Chambers, RC
通讯作者：
Chambers, RC
影响因子：
9.6
作者：
Mann, M;Chowdhury, B;Meyer, RJ
通讯作者：
Meyer, RJ
影响因子：
4.3
作者：
Kim, Robert;Meyer, Keith C
通讯作者：
Meyer, Keith C