Thioredoxin Protects Skin Flaps from Ischemia-Reperfusion Injury: A Novel Prognostic and Therapeutic Target

Background: Ischemia-reperfusion injury is inevitable during free-tissue transfer, causing oxidative damage and extensive apoptosis. Thioredoxin is an endogenous protein with antioxidant and antiapoptotic activity in a variety of tissues. This study aims to investigate the protective effects of human thioredoxin-1 on ischemia-reperfusion flaps, and its clinical application value. Methods: Sixteen clinical specimens of ischemia-reperfusion flaps were collected and assessed for apoptosis and thioredoxin-1 expression. Eighty mice were administered recombinant human thioredoxin-1 or saline intraperitoneally for 5 days before ischemia-reperfusion. Half of the mice were killed 24 hours after reperfusion. The flap tissues were harvested and detected for the changes of morphology, apoptosis, redox condition, and relative protein expression. The flap survival percentage of the remaining mice was consecutively observed within 7 days of reperfusion. Results: Thioredoxin-1 abundance was negatively correlated with ischemia-reperfusion-induced apoptosis in human samples and animal models. The survival rate of the ischemia-reperfusion flaps in mice increased significantly following recombinant human thioredoxin-1 pretreatment. Mitigated tissue damage, reduced apoptosis, and more antioxidant activity were observed in recombinant human thioredoxin-1-pretreated flaps. Western blot analysis revealed thioredoxin-1 depletion and a significant increase in apoptosis signal-regulating kinase 1, p-p38, and cleaved caspase-3 abundance in the ischemia-reperfusion flaps, whereas supplementation of recombinant human thioredoxin-1 significantly reduced the apoptosis-related protein expression. Conclusions: Thioredoxin-1 exerts its flap-protective role through redox regulation of reactive oxygen species scavenging and antiapoptotic signaling. The authors' research provides evidence that thioredoxin-1 may serve as a potential prognostic and therapeutic target for skin flap ischemia-reperfusion injury.