Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner.
Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner.
复制标题
抗纤溶剂氨甲环酸以纤溶酶独立的方式抑制内毒素诱导的 Tnfα 和 Il1α 基因的表达。
DOI：
10.1111/trf.17353
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发表时间：
2023
期刊：
影响因子：
2.9
通讯作者：
Prudovsky,Igor
中科院分区：
文献类型：
--
作者：
Kacer,Doreen;Machnitzky,Eva;Fung,Angus;Greene,Autumn;Carter,Damien;Rappold,Joseph;Prudovsky,Igor
氨甲环酸（TXA）是一种广泛应用于出血性创伤患者的抗纤溶药物。TXA的有益作用超过了对失血的抑制，并且包括减少炎症和水肿的能力。我们发现TXA抑制线粒体DNA的释放并增强线粒体呼吸。这些结果表明，TXA可以通过非纤溶酶依赖性机制发挥作用。为了解决这一假设，我们比较了TXA对脂多糖（LPS）诱导的促炎细胞因子在纤溶酶原（Plg）null和Plg杂合子mice.MethodsPlg null和Plg杂合子小鼠的表达的影响，注射LPS和TXA或LPS。4小时后，处死小鼠，从肝脏和心脏制备总RNA。采用特异性引物的真实的实时定量聚合酶链反应（Real-time quantitative polymerase chain reaction，RT-PCR）检测LPS和血栓素A（TXA）对小鼠肝、心组织中促炎细胞因子表达的影响。共注射TXA显著降低了LPS在Plg缺失和杂合小鼠中的作用。结论TXA对内毒素刺激的TNF α和IL 1 α表达的影响不依赖于对纤溶酶生成的抑制。这些结果表明，除了纤溶酶原/纤溶酶之外，TXA还具有其他生物学上重要的靶标。充分了解TXA广泛有益作用背后的分子机制及其靶点的未来鉴定可能会改善TXA在创伤、心脏和整形外科患者中的使用。
IntroductionTranexamic acid (TXA) is widely used as an antifibrinolytic agent in hemorrhagic trauma patients. The beneficial effects of TXA exceed the suppression of blood loss and include the ability to decrease inflammation and edema. We found that TXA suppresses the release of mitochondrial DNA and enhances mitochondrial respiration. These results allude that TXA could operate through plasmin‐independent mechanisms. To address this hypothesis, we compared the effects of TXA on lipopolysaccharide (LPS)‐induced expression of proinflammatory cytokines in plasminogen (Plg) null and Plg heterozygous mice.MethodsPlg null and Plg heterozygous mice were injected with LPS and TXA or LPS only. Four hours later, mice were sacrificed and total RNA was prepared from livers and hearts. Real time quantitative polymerase chain reaction with specific primers was used to assess the effects of LPS and TXA on the expression of pro‐inflammatory cytokines.ResultsLPS enhanced the expression ofTnfαin the livers and hearts of recipient mice. The co‐injection of TXA significantly decreased the effect of LPS both in Plg null and heterozygous mice. A similar trend was observed with LPS‐inducedIl1αexpression in hearts and livers.ConclusionsThe effects of TXA on the endotoxin‐stimulated expression ofTnfαandIl1αin mice do not depend on the inhibition of plasmin generation. These results indicate that TXA has other biologically important target(s) besides plasminogen/plasmin. Fully understanding the molecular mechanisms behind the extensive beneficial effects of TXA and future identification of its targets may lead to improvement in the use of TXA in trauma, cardiac, and orthopedic surgical patients.