Abstract：
BACKGROUND: Ischemia- reperfusion (I/R) injury-induced oxidative stress is a key factor in the pathogenesis of pressure ulcer formation. Ferroptosis is an iron-dependent programmed cell death that connects oxidative stress and inflammation in various diseases. Recent studies revealed the protective effect of inhibition of ferroptosis in I/R injury. However, the role of ferroptosis in cutaneous I/R injury remains elusive.
OBJECTIVE: To assess the role of ferroptosis in the progression of cutaneous I/R injury.
METHODS: Cutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro.
RESULTS: Inhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3+ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro, ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis.
CONCLUSIONS: Cutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury.
OBJECTIVE: To assess the role of ferroptosis in the progression of cutaneous I/R injury.
METHODS: Cutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro.
RESULTS: Inhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3+ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro, ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis.
CONCLUSIONS: Cutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury.
摘要：
背景：缺血再灌注（I/R）损伤诱导的氧化应激是压疮形成的重要发病因素。铁凋亡是一种铁依赖的程序性细胞死亡，它将各种疾病中的氧化应激和炎症联系起来。最近的研究揭示了抑制铁凋亡在I/R损伤中的保护作用。然而,铁凋亡在皮肤I/R损伤中的作用仍然难以捉摸。
目的：评估铁性凋亡在皮肤I/R损伤进展中的作用。
方法：在有或没有暴露于挥发性铁凋亡抑制剂的野生型小鼠中进行皮肤I/R损伤实验和组织病理学研究，TEMPO(2,2,6,6-四甲基哌啶-1-氧基)。体外研究了TEMPO对铁凋亡诱导细胞死亡和氧化应激的抑制作用。
结果：用TEMPO抑制铁凋亡显著减少皮肤I/R损伤后的溃疡形成。波动的铁死亡标记，如GPX4、ACSL4和4-HNE在I/R皮肤部位的表达，被TEMPO治疗逆转。抑制铁凋亡减少细胞凋亡，CD3+浸润淋巴细胞，并改善I/R皮肤部位的血管分布。铁凋亡的抑制也抑制了Nrf2活化的增强。体外，TEMPO治疗可显着改善小鼠成纤维细胞的铁凋亡和RSL3刺激对铁凋亡相关基因表达的激活。抑制铁凋亡还抑制了由铁凋亡引起的NOX2和HO-1mRNA水平的升高。
结论：皮肤I/R损伤诱导的铁性凋亡可能促进细胞死亡，血管丢失,炎症细胞浸润，和氧化应激。TEMPO抑制铁凋亡可能作为皮肤I/R损伤的新型治疗剂具有潜在的临床应用价值。
目的：评估铁性凋亡在皮肤I/R损伤进展中的作用。
方法：在有或没有暴露于挥发性铁凋亡抑制剂的野生型小鼠中进行皮肤I/R损伤实验和组织病理学研究，TEMPO(2,2,6,6-四甲基哌啶-1-氧基)。体外研究了TEMPO对铁凋亡诱导细胞死亡和氧化应激的抑制作用。
结果：用TEMPO抑制铁凋亡显著减少皮肤I/R损伤后的溃疡形成。波动的铁死亡标记，如GPX4、ACSL4和4-HNE在I/R皮肤部位的表达，被TEMPO治疗逆转。抑制铁凋亡减少细胞凋亡，CD3+浸润淋巴细胞，并改善I/R皮肤部位的血管分布。铁凋亡的抑制也抑制了Nrf2活化的增强。体外，TEMPO治疗可显着改善小鼠成纤维细胞的铁凋亡和RSL3刺激对铁凋亡相关基因表达的激活。抑制铁凋亡还抑制了由铁凋亡引起的NOX2和HO-1mRNA水平的升高。
结论：皮肤I/R损伤诱导的铁性凋亡可能促进细胞死亡，血管丢失,炎症细胞浸润，和氧化应激。TEMPO抑制铁凋亡可能作为皮肤I/R损伤的新型治疗剂具有潜在的临床应用价值。
