Prudovsky Lab & Tissue Repair and Regeneration Program
The Prudovsky laboratory studies molecular mechanisms underlying tissue repair.
Mitochondria as a Target for Trauma Repair
Figure 1: Tranexamic acid (TXA) increases mitochondrial respiration and ATP production in endothelial cells: study using the Seahorse analyzer.
Severe trauma results in the dysregulation of mitochondrial respiration leading to cells damage, and systemic inflammation. The search for efficient methods to enhance mitochondria function can result in the improvement of trauma treatment methods. Tranexamic acid (TXA) is a popular anti-fibrinolytic drug widely used in hemorrhagic trauma, cardiovascular surgery and in orthopedic surgery patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies demonstrated broad life-saving effects of TXA in trauma, superior to those of other anti-fibrinolytic agents. Besides preventing fibrinolysis and resulting blood loss, TXA has been reported to suppress post-traumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, very little is known about cell and molecular mechanisms underlying its extensive activities. The major events taking place after severe trauma, are metabolic shock, release to the bloodstream of pro-inflammatory Damage Associated Molecular Patterns (DAMP), and shedding of endothelial glycocalyx.
In our studies in collaboration with Drs. Damien Carter, Joseph Rappold, and Robert Kramer (all surgeons from Maine Medical Center), we have found that TXA enhances the efficiency of mitochondrial respiration in endothelial cells (Figure 1) increases the length of mitochondria (Figure 2), suppresses the burn injury-induced release of a major DAMP, mitochondrial DNA to mouse bloodstream (Figure 3), and decreases the burn-induced lung inflammation in mice (Figure 4). Interestingly, using plasminogen null mice we found that inhibition of the endotoxin-induced expression of two major proinflammatory cytokines, IL1alpha (Figure 5) and TNFalpha (not shown) is not dependent on the inhibition of plasminogen, the classical target of TXA. We suggest that enhancement of mitochondrial respiration by TXA suppresses DAMP release and metabolic stress, resulting in decreased inflammation and edema, and improved outcomes after severe trauma. (Figure 6). We are currently studying the effects of TXA on the healing of burn wounds and on burn-induced edema. The effects of other compounds enhancing mitochondrial respiration on burn injury and other types of severe trauma are also studied in our laboratory.
Figure 2. TXA treatment increases the length of mitochondria