PDF(Pubmed)
Abstract：
UNASSIGNED: Radiation-induced fibrosis (RIF) is a debilitating sequelae of radiation therapy that has been shown to improve with topical treatment with the iron chelator deferoxamine (DFO). We investigated whether DFO exerts this effect through attenuation of ferroptosis, a recently described iron-dependent pathway of cell death.
UNASSIGNED: Adult C57BL/6J mice were treated with topical DFO or ferrostastin-1 (Fer-1) and irradiated with 30 Grays of ionizing radiation to the dorsal skin to promote development of chronic RIF. Immunofluorescent staining with 4-hydroxynonenal (4-HNE) antibody was carried out directly following irradiation to assess ferroptosis activity. Perfusion testing with laser Doppler was performed throughout the healing interval. Eight weeks following radiation, dorsal skin was harvested and analyzed histologically and biomechanically.
UNASSIGNED: Immunohistochemical staining demonstrated lower presence of 4-HNE in non-irradiated skin, DFO-treated skin, and Fer-1-treated skin compared to irradiated, untreated skin. DFO resulted in histological measurements (dermal thickness and collagen content) that resembled normal skin, while Fer-1 treatment yielded less significant improvements. These results were mirrored by analysis of extracellular matrix ultrastructure and biomechanical testing, which recapitulated the ability of topical DFO treatment to alleviate RIF across these parameters while Fer-1 resulted in less notable improvement. Finally, perfusion levels in DFO treated irradiated skin were similar to measurements in normal skin, while Fer-1 treatment did not impact this feature.
UNASSIGNED: Ferroptosis contributes to the development of RIF and attenuation of this process leads to reduced skin injury. DFO further improves RIF through additional enhancement of perfusion not seen with Fer-1.
UNASSIGNED: Adult C57BL/6J mice were treated with topical DFO or ferrostastin-1 (Fer-1) and irradiated with 30 Grays of ionizing radiation to the dorsal skin to promote development of chronic RIF. Immunofluorescent staining with 4-hydroxynonenal (4-HNE) antibody was carried out directly following irradiation to assess ferroptosis activity. Perfusion testing with laser Doppler was performed throughout the healing interval. Eight weeks following radiation, dorsal skin was harvested and analyzed histologically and biomechanically.
UNASSIGNED: Immunohistochemical staining demonstrated lower presence of 4-HNE in non-irradiated skin, DFO-treated skin, and Fer-1-treated skin compared to irradiated, untreated skin. DFO resulted in histological measurements (dermal thickness and collagen content) that resembled normal skin, while Fer-1 treatment yielded less significant improvements. These results were mirrored by analysis of extracellular matrix ultrastructure and biomechanical testing, which recapitulated the ability of topical DFO treatment to alleviate RIF across these parameters while Fer-1 resulted in less notable improvement. Finally, perfusion levels in DFO treated irradiated skin were similar to measurements in normal skin, while Fer-1 treatment did not impact this feature.
UNASSIGNED: Ferroptosis contributes to the development of RIF and attenuation of this process leads to reduced skin injury. DFO further improves RIF through additional enhancement of perfusion not seen with Fer-1.
摘要：
背景技术辐射诱导的纤维化(RIF)是放射疗法的一种使人衰弱的后遗症,其已被证明与铁螯合剂去铁胺(DFO)的局部治疗一起改善。我们研究了DFO是否通过减弱铁中毒来发挥这种作用，最近描述的铁依赖性细胞死亡途径。方法对成年C57BL/6J小鼠进行局部DFO或ferrostastin-1（Fer-1）治疗，并对背部皮肤进行30格来电离辐射，以促进慢性RIF的发展。照射后直接用4-羟基壬烯醛（4-HNE）抗体进行免疫荧光染色，以评估铁凋亡活性。在整个愈合间隔内进行激光多普勒灌注测试。辐射后八周，收集背侧皮肤，并进行组织学和生物力学分析。结果免疫组织化学染色显示未照射皮肤中4-HNE的存在较低，DFO处理过的皮肤，和Fer-1处理过的皮肤相比，未经处理的皮肤。DFO导致组织学测量（真皮厚度和胶原蛋白含量），类似于正常皮肤，而Fer-1治疗效果改善不明显。这些结果通过分析细胞外基质超微结构和生物力学测试得到反映，它概括了局部DFO治疗在这些参数中缓解RIF的能力，而Fer-1导致不太明显的改善。最后,DFO处理的辐照皮肤的灌注水平与正常皮肤的测量结果相似，而Fer-1治疗并不影响这一特征。结论Ferroptosis有助于RIF的发生发展，该过程的减弱导致皮肤损伤减少。DFO通过Fer-1未见的灌注的额外增强进一步改善了RIF。
