The Role of Statins in Cutaneous Wound Healing

描述（由申请人提供）：高血压和肥胖是抑制伤口愈合的众所周知的因素。相反，他汀类药物，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，降低循环胆固醇水平，改善组织修复。最近，我们已经确定了他汀类药物加速伤口愈合的分子机制。我们发现，他汀类药物通过阻断焦磷酸法呢酯（FPP）的合成促进伤口愈合，FPP是甲羟戊酸途径中的重要分支点中间体，对于甾醇和异戊二烯化细胞代谢物的合成至关重要，从而导致胆固醇合成。FPP通过作为抗炎剂，即糖皮质激素受体（GR）的真正激动剂，抑制体外角质形成细胞迁移和离体伤口愈合，而他汀类药物逆转这种作用。因此，我们推测他汀类药物可能通过调节炎症反应加速伤口愈合。将使用局部他汀类药物对高脂血症和健康（血脂正常）猪伤口愈合模型进行体内试验。一旦确定了他汀类药物的最佳局部剂量（目的1），我们将通过测量高脂血症和正常脂血症猪伤口模型中促炎细胞因子和抗炎细胞因子、GR-磷酸化以及嗜中性粒细胞和巨噬细胞浸润的水平来确定他汀类药物对炎症反应的影响（目的2A）。最近，他汀类药物被发现具有抗微生物作用。细菌感染是伤口愈合最常见的并发症之一，已知会抑制这一过程。因此，我们还将测试局部他汀类药物单独或与全身性他汀类药物组合是否加速细菌感染伤口的伤口愈合（目的2B）。拟议研究的高度影响是多因素的：1）它将提供一个经验证的体内实验模型，以研究与肥胖和高胆固醇水平相关的皮肤伤口愈合和感染; 2）为他汀类药物治疗伤口愈合障碍的潜在局部使用开发临床前证据，以及3）为他汀类药物可能影响全身使用患者伤口愈合能力的机制提供了新的见解。

DESCRIPTION (provided by applicant): Hyperlipidemia and obesity are well known factors that inhibit wound healing. Conversely, statins, the 3- hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that lower circulating cholesterol levels improve tissue repair. Recently, we have identified molecular mechanism by which statins accelerate wound healing. We found that statins promote wound healing, via blocking the synthesis of Farnesyl pyrophosphate (FPP), an important branch-point intermediate in the mevalonate pathway, essential for synthesis of sterols and isoprenylated cellular metabolites leading to cholesterol synthesis. FPP inhibits keratinocyte migration in vitro and wound healing ex vivo by acting as an anti-inflammatory agent, i.e. a bona fide agonist for glucocorticoid receptor (GR), whereas statins reverse this effect. Therefore, we hypothesize that statins may accelerate wound healing by modulating the inflammatory response. This hypothesis will be tested using topical statins on hyperlipidemic and healthy (normolipidemic) porcine wound healing model in vivo. Once an optimal topical dose of statins is determined (Aim 1) we will determine the effects of statins on the inflammatory response by measuring levels of pro- and anti-inflammatory cytokines, GR- phosphorylation as well as neutrophil and macrophage infiltration in hyperlipidemic and normolipidemic porcine wound model (Aim 2A). Recently, statins were found to have anti-microbial effect. Bacterial infection is one of the most common complications of wound healing, known to inhibit this process. Thus, we will also test if topical statins alone or in combination with systemic statins, accelerate wound healing of bacterially-infected wounds (Aim 2B). The high impact of proposed study is multi-factorial: 1) it will provide a validated in vivo experimental models to study cutaneous wound healing and infection related to obesity and high cholesterol levels; 2) develop pre- clinical evidence for potential topical use of statins to treat wound healing disorders and 3) provide new insights into the mechanism by which statins may impact healing ability of wounds in patients who are using them systemically.