Kuhn Joseph, Sultan Darren L, Waqas Bukhtawar, Ellison Trevor, Kwong Jennifer, Kim Camille, Hassan Absara, Rabbani Piul S, Ceradini Daniel J
Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, N.Y.
Plast Reconstr Surg Glob Open. 2020 Nov 20;8(11):e3006. doi: 10.1097/GOX.0000000000003006. eCollection 2020 Nov.
Chronic venous insufficiency (CVI) stems from venous hypertension, extravasation of blood, and iron-rich skin deposits. The latter is central to ulcer development through generating reactive oxygen species (ROS) that drive persistent local inflammation and the development of lipodermatosclerosis. The ability to study CVI cutaneous inflammation is fundamental to advancing therapies. To address this end, a novel protocol was adapted to investigate cutaneous wound healing in iron-induced inflammation.
Mice were injected subcutaneously or intraperitoneally with iron-dextran, and excisional wounding was performed. Histologic and biomolecular analysis was performed.
Iron loading was associated with dense iron deposits similar to those in chronic venous stasis. Subcutaneous but not intraperitoneal loading resulted in dermal collagen expansion. Iron overload was associated with atypical antioxidant expression as compared to vehicle controls ( < 0.0001) as well as delayed wound healing by 3-4 days. A potent activator of Nuclear factor erythroid 2-related factor 2 (Nrf2), a major transcriptional regulator of redox status, was applied to establish therapeutic efficacy. Nrf2 activation in the wound resulted in significant reduction of closure times across all experimental arms. Antioxidant expression following topical treatment was significantly increased for intraperitoneally iron-loaded mice ( < 0.0001) but did not achieve significance for the subcutaneously-loaded animals.
We have characterized a novel model of cutaneous iron-overload designed to advance our understanding of dysfunctional wound healing in CVI. Cutaneous changes of iron overload coincide with redox imbalance and delayed wound healing. By activating Nrf2, we demonstrate the regenerative potential of pro-antioxidant mediators in treating CVI related wound complications.
慢性静脉功能不全（CVI）源于静脉高压、血液外渗和富含铁的皮肤沉积物。后者通过产生活性氧（ROS）驱动持续的局部炎症和脂肪皮肤硬化的发展，对溃疡形成至关重要。研究CVI皮肤炎症的能力是推进治疗的基础。为了实现这一目标，采用了一种新方案来研究铁诱导炎症中的皮肤伤口愈合。
给小鼠皮下或腹腔注射右旋糖酐铁，然后进行切除性创伤。进行组织学和生物分子分析。
铁负荷与类似于慢性静脉淤滞中的致密铁沉积物有关。皮下注射而非腹腔注射导致真皮胶原扩张。与载体对照相比，铁过载与非典型抗氧化剂表达相关（<0.0001），并且伤口愈合延迟3 - 4天。应用核因子红细胞2相关因子2（Nrf2）的强效激活剂，Nrf2是氧化还原状态的主要转录调节因子，以确定治疗效果。伤口中的Nrf2激活导致所有实验组的闭合时间显著缩短。对于腹腔注射铁的小鼠，局部治疗后的抗氧化剂表达显著增加（<0.0001），但对于皮下注射铁的动物未达到显著水平。
我们已经描述了一种新型的皮肤铁过载模型，旨在增进我们对CVI中功能失调的伤口愈合的理解。铁过载的皮肤变化与氧化还原失衡和伤口愈合延迟相一致。通过激活Nrf2，我们证明了促抗氧化介质在治疗CVI相关伤口并发症方面的再生潜力。
