The Role of Statins in Cutaneous Wound Healing

描述(由申请人提供)：高脂血症和肥胖是阻碍伤口愈合的众所周知的因素。相反，他汀类药物，即3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，可以降低循环中的胆固醇水平，促进组织修复。最近，我们已经确定了他汀类药物促进伤口愈合的分子机制。我们发现，他汀类药物通过抑制法呢基焦磷酸(FPP)的合成来促进伤口愈合，法尼基焦磷酸是甲氧戊酸途径的重要分支点中间体，对于合成甾醇和异戊二烯基化的细胞代谢物导致胆固醇合成是必不可少的。FPP通过作为抗炎剂，即糖皮质激素受体(GR)的真正激动剂，在体外抑制角质形成细胞的迁移和体外创面愈合，而他汀类药物则逆转这一作用。因此，我们推测他汀类药物可能通过调节炎症反应来加速伤口愈合。这一假说将在体内使用局部他汀类药物在高脂血症和健康(正常血脂)猪伤口愈合模型上进行验证。一旦确定了他汀类药物的最佳局部剂量(目标1)，我们将通过测量高脂和低脂猪创伤模型中促炎症和抗炎细胞因子、GR磷酸化以及中性粒细胞和巨噬细胞的浸润水平来确定他汀类药物对炎症反应的影响(目标2A)。近年来，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，我们还将测试外用他汀类药物是否单独或与全身他汀类药物联合使用，加速细菌感染伤口的愈合(目标2B)。拟议研究的高度影响是多方面的：1)它将提供一个经过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)开发临床前证据，证明他汀类药物可能用于治疗伤口愈合障碍；3)为他汀类药物可能影响全身使用他汀类药物患者伤口愈合能力的机制提供新的见解。 与公共卫生相关：许多患者(特别是老年人、肥胖症和/或糖尿病患者)目前正在接受各种胆固醇合成调节剂、他汀类药物的治疗，这可能会影响他们愈合伤口的能力。本研究将对他汀类药物的多效性及其在体内高胆固醇和/或伤口感染条件下调节炎症反应和促进创面愈合的机制提供更好的认识，为创面修复疾病的治疗提供新的治疗途径。

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.