Drysch Marius, Fiedler Alexander, Kurbacher Tabea, Schmidt Sonja Verena, Reinkemeier Felix, Puscz Flemming, Becerikli Mustafa, Fueth Maria, Weskamp Pia, Lehnhardt Marcus, Wallner Christoph, Sogorski Alexander
Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
Department of Gynecology and Obstetrics, St. Elisabeth-Hospital, Ruhr University Bochum, Bochum, Germany.
J Cell Mol Med. 2025 Aug;29(15):e70739. doi: 10.1111/jcmm.70739.
Ischemia-reperfusion injury remains a major challenge in free flap surgery, contributing to oxidative stress, inflammation, and cell death that impair tissue viability and outcomes. Remote ischemic preconditioning (RIPC) has emerged as a potential protective strategy by modulating cellular stress responses, but its molecular mechanisms in free flaps remain incompletely understood. We prospectively enrolled 36 female patients undergoing autologous breast reconstruction with mainly deep inferior epigastric perforator (DIEP) free flaps, randomised into three groups: No RIPC, Early RIPC (24 h preconditioning), and Late RIPC (1 h preconditioning). Tissue samples were collected pre-ischemia and post-reperfusion for immunohistochemical and multiplex protein analyses. RIPC did not reduce oxidative stress markers, as 4-hydroxynonenal (4-HNE) levels were comparable across groups, while 3-nitrotyrosine levels paradoxically increased after RIPC. Early RIPC selectively modulated cell death pathways, with decreased expression of mitochondrial apoptotic marker caspase 9 and reduced necroptotic activation of mixed lineage kinase domain-like protein (MLKL) after reperfusion. Caspase 8 showed a transient modulation, suggesting effects on apoptosis-necroptosis crosstalk. Cyclophilin A levels were elevated after reperfusion in RIPC groups, indicating an adaptive stress response. These findings suggest that early RIPC exerts selective protection by modulating apoptosis and necroptosis, rather than broadly reducing oxidative stress. RIPC may represent a targeted strategy to improve free flap survival in reconstructive surgery.
缺血再灌注损伤仍然是游离皮瓣手术中的一个重大挑战，它会导致氧化应激、炎症和细胞死亡，从而损害组织活力和手术效果。远程缺血预处理（RIPC）已成为一种潜在的保护策略，可通过调节细胞应激反应来实现，但在游离皮瓣中的分子机制仍未完全明确。我们前瞻性地纳入了36例接受自体乳房重建且主要采用腹壁下深动脉穿支（DIEP）游离皮瓣的女性患者，随机分为三组：无RIPC组、早期RIPC组（预处理24小时）和晚期RIPC组（预处理1小时）。在缺血前和再灌注后采集组织样本进行免疫组织化学和多重蛋白质分析。RIPC并未降低氧化应激标志物水平，因为各组间4-羟基壬烯醛（4-HNE）水平相当，而RIPC后3-硝基酪氨酸水平反而升高。早期RIPC选择性地调节细胞死亡途径，再灌注后线粒体凋亡标志物半胱天冬酶9的表达降低，混合谱系激酶结构域样蛋白（MLKL）的坏死性凋亡激活减少。半胱天冬酶8表现出短暂调节，提示对凋亡-坏死性凋亡相互作用有影响。RIPC组再灌注后亲环素A水平升高，表明存在适应性应激反应。这些发现表明，早期RIPC通过调节凋亡和坏死性凋亡发挥选择性保护作用，而不是广泛降低氧化应激。RIPC可能是一种改善重建手术中游离皮瓣存活的靶向策略。
