Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner

Authors

Doreen Kacer, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.Follow
Eva Machnitzky, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.
Angus Fung, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.
Autumn Greene, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.
Damien Carter, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.Follow
Joseph Rappold, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.Follow
Igor Prudovsky, Maine Health Institute for Research, 81 Research Dr., Scarborough, ME, USA.Follow

Document Type

Article

Publication Date

4-18-2023

Institution/Department

Trauma & Acute Care Surgery

Journal Title

Transfusion

Abstract

INTRODUCTION: Tranexamic acid (TXA) is widely used as 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. METHODS: Plg 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. RT-qPCR with specific primers was used to assess the effects of LPS and TXA on the expression of pro-inflammatory cytokines. RESULTS: LPS enhanced the expression of Tnfα in 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-induced Il1α expression in hearts and livers. CONCLUSIONS: The effects of TXA on the endotoxin-stimulated expression of Tnfα and Il1α in 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. This article is protected by copyright. All rights reserved.

Recommended Citation

Kacer D, Machnitzky E, Fung A, et al. Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner [published online ahead of print, 2023 Apr 18]. Transfusion. 2023;10.1111/trf.17353. doi:10.1111/trf.17353