The Role of Statins in Cutaneous Wound Healing

描述（申请人提供）：高脂血症和肥胖是众所周知的抑制伤口愈合的因素。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，促进组织修复。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法尼酯焦磷酸盐（FPP）的合成来促进伤口愈合，FPP是甲羟戊酸途径中重要的分支点中间体，对于合成固醇和导致胆固醇合成的异戊烯基化细胞代谢物至关重要。FPP作为抗炎剂，即糖皮质激素受体（GR）的真正激动剂，在体外抑制角化细胞迁移和体外伤口愈合，而他汀类药物逆转了这一作用。因此，我们假设他汀类药物可能通过调节炎症反应来加速伤口愈合。这一假设将在体内使用局部他汀类药物对高脂血症和健康（降脂）猪伤口愈合模型进行检验。一旦确定了他汀类药物的最佳外用剂量（目的1），我们将通过测量高脂血症和降脂症猪伤口模型中促炎性和抗炎性细胞因子、GR-磷酸化以及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，他汀类药物被发现有抗菌作用。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使用或与全身他汀类药物联合使用是否能加速细菌感染伤口的伤口愈合（Aim 2B）。该研究的高影响是多方面的：1)它将提供一个有效的体内实验模型来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)为局部使用他汀类药物治疗伤口愈合障碍提供临床前证据；3)为他汀类药物可能影响全身使用他汀类药物的患者伤口愈合能力的机制提供新的见解。

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. PUBLIC HEALTH RELEVANCE: Number of patients (particularly elderly, obese and/or diabetic) are currently treated by various modulators of cholesterol synthesis, statins, which may impact their ability to heal wounds. This study will provide a better understanding of the pleiotropic effects of statins as well as the mechanisms by which they modulate inflammatory response and accelerate wound healing in vivo, in the presence of high-cholesterol and/or wound infection, which may provide novel therapeutic approach for treatment of wound healing disorders.