The Role of Statins in Cutaneous Wound Healing

他汀类药物在皮肤伤口愈合中的作用

基本信息

批准号：
8191602
负责人：
Marjana Tomic-Canic
金额：
$ 17.21万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-25 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8191602
关键词：
Acute Agonist Anti-Inflammatory Agents Anti-inflammatory Antimicrobial Effect Bacterial Infections Cholesterol Clinical Coenzyme A Collagen Communities Cutaneous Data Deposition Disease Dose Elderly Enzyme-Linked Immunosorbent Assay Experimental Models Family suidae Glucocorticoid Receptor Goals Granulation Tissue Healed Hydroxyl Radical Hyperlipidemia Impairment In Vitro Incidence Individual Infiltration Inflammatory Inflammatory Response Knowledge Lead Learning Measures Mediating Modeling Molecular Morbidity - disease rate Nuclear Obesity Oxidoreductase Pain Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Process Regulation Research Role Site Skin Specimen Sterols Testing Therapeutic Uses Thick Topical application Wound Healing Wound Infection angiogenesis antimicrobial base cytokine diabetic experience farnesyl pyrophosphate healing high risk improved in vivo in vivo Model inhibitor/antagonist insight keratinocyte macrophage methicillin resistant Staphylococcus aureus mevalonate migration neutrophil novel therapeutic intervention novel therapeutics pre-clinical wound

项目摘要

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.

描述（由申请人提供）：高脂血症和肥胖是抑制伤口愈合的众所周知的因素。相反，他汀类药物是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可改善组织修复。最近，我们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止Farnesyl焦磷酸盐（FPP）的合成来促进伤口愈合，这是甲醛酸途径中重要的分支点中间体，对于固醇和异丙烯基化的细胞代谢物的合成至关重要。 FPP通过充当抗炎剂，即糖皮质激素受体（GR）的真正的激动剂，在体外抑制角质形成细胞迁移，并通过体内抑制伤口愈合，而他汀类药物却扭转了这种作用。因此，我们假设他汀类药物可以通过调节炎症反应来加速伤口愈合。该假设将在体内使用高脂症和健康（正常脂肪）猪伤口愈合模型的局部汀类药物进行测试。一旦确定了他汀类药物的最佳局部剂量（目标1），我们将通过测量促疾病和抗炎细胞因子的水平，GR-磷酸化以及中性粒细胞以及巨噬细胞浸润性在高脂症和非脂肪症伤口模型（AIM 2A）来确定他汀类药物对炎症反应的影响。最近，他汀类药物具有抗菌作用。细菌感染是伤口愈合的最常见并发症之一，已知会抑制这一过程。因此，我们还将测试局部他汀类药物是单独的还是与全身性汀类药物结合的，加速了细菌感染的伤口的伤口愈合（AIM 2B）。拟议研究的高影响是多因素：1）它将提供经过验证的体内实验模型，以研究与肥胖和高胆固醇水平有关的皮肤伤口愈合和感染； 2）为他汀类药物治疗伤口愈合疾病的潜在局部使用而开发临床证据，3）对他汀类药物可能影响系统使用的患者伤口愈合能力的机制提供了新的见解。公共卫生相关性：目前，胆固醇合成的各种调节剂，他汀类药物的各种调节剂目前对患者的数量（尤其是老年人，肥胖和/或糖尿病患者）进行治疗，这可能会影响其治愈伤口的能力。这项研究将更好地理解他汀类药物的多效作用，以及在存在高胆固醇和/或伤口感染的情况下它们调节炎症反应并加速体内伤口愈合的机制，这可能为治疗伤口愈合疾病的治疗方法提供了新的治疗方法。