Burn Injury Alters Epidermal Cholinergic Mediators and Increases HMGB1 and Caspase 3 in Autologous Donor Skin and Burn Margin.
Burn Injury Alters Epidermal Cholinergic Mediators and Increases HMGB1 and Caspase 3 in Autologous Donor Skin and Burn Margin.
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DOI：
10.1097/shk.0000000000000752
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Radek KA
中科院分区：
文献类型：
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作者：
Holmes CJ;Plichta JK;Gamelli RL;Radek KA
烧伤创面愈合并发症，如移植失败或感染，是烧伤患者发病率和死亡率的主要来源。局部烧伤损伤改变自体供体皮肤和周围烧伤边缘的表皮屏障功能的机制在很大程度上是不确定的。我们假设表皮胆碱能系统的缺陷可能会损害表皮屏障功能和先天性免疫反应。其目的是确定表皮胆碱能途径的改变，以及与炎症和细胞死亡相关的下游靶点。我们确定，在供体和烧伤边缘皮肤中，α7烟碱乙酰胆碱受体（CHRNA 7）的蛋白水平（而非基因表达）均显著降低。此外，内源性别构调节剂CHRNA 7，分泌的哺乳动物Ly-6/尿激酶型纤溶酶原激活物受体相关蛋白-1（SLURP 1）和乙酰胆碱的基因和蛋白水平显着升高供体和烧伤边缘皮肤。作为nAChR激活的炎症和细胞死亡靶点的下游蛋白，我们发现供体和烧伤边缘皮肤中的表皮高迁移率族蛋白1（HMGB 1）和半胱天冬酶3显著升高。最后，我们采用了一种新的体外角质形成细胞烧伤模型，以建立烧伤影响这些胆碱能介质及其下游靶点的基因表达。这些结果表明，供体和烧伤边缘皮肤中胆碱能介质和炎症/凋亡分子的缺陷可能直接导致烧伤患者移植失败或感染。
Burn wound healing complications, such as graft failure or infection, are a major source of morbidity and mortality in burn patients. The mechanisms by which local burn injury alters epidermal barrier function in autologous donor skin and surrounding burn margin are largely undefined. We hypothesized that defects in the epidermal cholinergic system may impair epidermal barrier function and innate immune responses. The objective was to identify alterations in the epidermal cholinergic pathway, and their downstream targets, associated with inflammation and cell death. We established that protein levels, but not gene expression, of the α7 nicotinic acetylcholine receptor (CHRNA7) were significantly reduced in both donor and burn margin skin. Furthermore, the gene and protein levels of an endogenous allosteric modulator of CHRNA7, secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP1) and acetylcholine were significantly elevated in donor and burn margin skin. As downstream proteins of inflammatory and cell death targets of nAChR activation, we found significant elevations in epidermal High Mobility Group Box Protein 1 (HMGB1) and caspase 3 in donor and burn margin skin. Lastly, we employed a novel in vitro keratinocyte burn model to establish that burn injury influences the gene expression of these cholinergic mediators and their downstream targets. These results indicate that defects in cholinergic mediators and inflammatory/apoptotic molecules in donor and burn margin skin may directly contribute to graft failure or infection in burn patients.