Direct thrombin inhibitors as alternatives to heparin to preserve lung growth and function in a murine model of compensatory lung growth.
Direct thrombin inhibitors as alternatives to heparin to preserve lung growth and function in a murine model of compensatory lung growth.
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DOI：
10.1038/s41598-022-25773-3
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发表时间：
2022-12-07
影响因子：
4.6
通讯作者：
Puder M
中科院分区：
文献类型：
--
作者：
Tsikis ST;Hirsch TI;Fligor SC;Pan A;Joiner MM;Devietro A;Mitchell PD;Kishikawa H;Gura KM;Puder M
先天性横隔疝(CDH)的婴儿可能需要体外循环和全身抗凝。搭桥期间快速的肺生长对生存至关重要。此前，我们在代偿性肺生长(CLG)的小鼠模型中证明了肝素损害了肺的生长和功能。我们研究了直接凝血酶抑制剂(DTI)比伐卢定和阿加曲班的作用。体外检测肺内皮细胞增殖和凋亡情况。对C57BL/6小鼠进行左全肺切除，皮下植入渗透泵。术后第8天分别给予生理盐水(对照组)、比伐卢定、阿加曲班或肝素。肝素在体外抑制内皮细胞的增殖，显著减少体内肺体积，而比伐鲁丁和阿加曲班则能保护肺的生长。这些发现与形态计量学分析上的牙槽化改变有关。跑步机运动耐量试验显示肝素化小鼠的运动能力受损；比伐卢定/阿加曲班不影响运动耐量。在肺蛋白质分析中，肝素减少了血管生成信号，而比伐卢定或阿加曲班不影响这一点。综上所述，这些数据支持将DTI作为肝素的替代品用于CDH患者搭桥手术中的全身抗凝。基于这项工作，有必要对肝素和DTI对CDH预后的影响进行临床研究。
Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.
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DOI：
10.3390/molecules20046342
发表时间：
2015-04-10
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Chiodelli P;Bugatti A;Urbinati C;Rusnati M
通讯作者：
Rusnati M
影响因子：
3.7
作者：
Kapur, Navin K.;Shenoy, Chetan;Jaffe, Iris Z.
通讯作者：
Jaffe, Iris Z.
影响因子：
3.5
作者：
Asanuma, K;Wakabayashi, H;Uchida, A
通讯作者：
Uchida, A
影响因子：
6.7
作者：
Li, Jin-ping;Vlodavsky, Israel
通讯作者：
Vlodavsky, Israel
影响因子：
6
作者：
Kassel, Karen M.;Sullivan, Bradley P.;Luyendyk, James P.
通讯作者：
Luyendyk, James P.