Mechanisms of Impaired Wound Healing Due to Ischemia

缺血导致伤口愈合受损的机制

• 批准号: 7796534
• 负责人: Lisa J Gould
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796534
• 关键词: 3-nitrotyrosine; Acute; Affect; Age; Age-Months; Aged, 80 and over; Aging; American; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Biological Assay; Biological Availability; Buffers; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Collagen; Comorbidity; Confocal Microscopy; Cuprozinc Superoxide Dismutase; Data; Diabetes Mellitus; Elderly; Endothelial Cells; Enzymes; Epidemic; Epithelial Cells; Equilibrium; Excision; Extracellular Matrix; Fibroblasts; Foundations; Gelatinase B; Generations; Glutamate-Cysteine Ligase; Glutathione; Goals; Healed; Health; Health system; Healthcare; Healthcare Systems; Heart Diseases; Homeostasis; Human; Hydrogen Peroxide; Hyperoxia; Hypoxia; Immunoblotting; Immunohistochemistry; Impaired wound healing; Incidence; Indium; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intermittent Claudication; Interstitial Collagenase; Ischemia; Isoenzymes; Lead; Life; Limb structure; Liquid substance; Literature; Lower Extremity; Lucigenin; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Measures; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; NBL1 gene; Natural regeneration; Necrosis; Nitrates; Nitric Oxide; Nitrites; Nitrogen; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Perfusion; Peripheral arterial disease; Peroxonitrite; Physiological; Play; Population; Predisposition; Prevalence; Procedures; Process; Production; Protease Inhibitor; Protein Isoforms; Proteins; Public Health; Rattus; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Reperfusion Therapy; Residual state; Role; Signaling Molecule; Skin; Skin Aging; Stress; Superoxide Dismutase; Superoxides; Surgical Flaps; System; Testing; Time; Tissue Extracts; Tissue Model; Tissues; Vascular Diseases; Vascular blood supply; Venous Insufficiency; Veterans; Water; Wound Healing; abstracting; angiogenesis; catalase; cell motility; cost; cytokine; effective therapy; enzyme activity; healing; improved; inhibitor/antagonist; keratinocyte; mRNA Expression; middle age; migration; mimetics; nitration; novel; oxidation; oxidative damage; pressure; prevent; protein expression; response; superoxide dismutase 1; synthetic enzyme; tissue trauma; wound; young adult

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Treatment of chronic, non-healing wounds is a major public health issue that is growing as our population ages. It is estimated that 5 million Americans suffer from chronic wounds, costing the US health system $20 to 25 billion a year. Chronic wounds currently affect about 15% of older Americans. However, because the number of individuals 65 and older is the fastest growing population and co-morbid conditions that result in tissue ischemia, such as heart disease, peripheral arterial disease and diabetes, are more common in the elderly, this figure is expected to steadily increase. The central hypothesis of this project is that tissue ischemia disrupts the delicate balance between the production of reactive oxygen species and their removal by endogenous antioxidants, resulting in oxidative stress, altered composition of the extracellular matrix and impaired healing. We will also explore the hypothesis that despite physiologic changes associated with aging that affect wound healing, the primary reason for the increased prevalence of impaired wound healing in the elderly is tissue ischemia. Using a rat ischemic flap model we will: 1) Test the hypothesis that dysregulation of the endogenous antioxidant system results in a net excess of reactive oxygen species in the ischemic wound, 2) Test the hypothesis that manipulating the redox balance in ischemic wounds can improve healing. 3) Test the hypothesis that the redox balance affects matrix metalloproteinase activity. Procedures to be Used: The rat model of tissue ischemia developed and validated by Dr. Gould (Wound Repair and Regeneration, 2005) will be used to measure oxidative stress, endogenous antioxidants, proteases, and protease inhibitors in ischemic and non-ischemic wounds of young, middle aged and old rats, comparing these factors to the extracellular matrix composition. Exogenous antioxidant mimetics will be tested for their ability to alter the redox balance and improve wound healing. The contribution of specific cell populations in redox homeostasis will be characterized using a novel live tissue assay. To further characterize the mechanisms that impair cellular function during oxidative stress and verify that these mechanisms are consistent between species, primary human fibroblasts from donors of different ages will be grown under conditions of hypoxia, normoxia and hyperoxia. Utilizing specific inhibitors of endogenous antioxidants, levels of inflammatory mediators, proteases, matrix production and destruction and the impact on cell migration will be determined. Significance: Our long term goal is to elucidate the cellular mechanisms that result in chronic wounds so that rational therapies can be developed to improve healing or prevent these wounds altogether. The molecular changes that occur in wound healing, particularly in the elderly who more commonly have tissue ischemia, are poorly understood. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care/Relevance: 9.2 million veterans are age 65 or older, representing 38 percent of the total veteran population. This figure is three times that of the general U.S. population. Thus, healthcare for the aging veteran population is a major challenge. Wounds with poor blood supply are some of the most difficult wounds to treat and are becoming an increasing problem in the elderly. By understanding the basic mechanisms that are responsible for impaired wound healing in ischemic tissue we will be equipped to develop rational and effective treatments, resulting in decreased cost and morbidity for our veterans in the years to come.

描述（由申请人提供）： 慢性、不愈合伤口的治疗是一个主要的公共卫生问题，随着我们人口的老龄化而不断增长。据估计，500万美国人患有慢性伤口，每年花费美国卫生系统200亿至250亿美元。慢性创伤目前影响着大约15%的美国老年人。然而，由于65岁及以上的人数是增长最快的人口，导致组织缺血的并发症，如心脏病，外周动脉疾病和糖尿病，在老年人中更常见，预计这一数字将稳步增加。 该项目的中心假设是，组织缺血破坏了活性氧的产生和内源性抗氧化剂对其的清除之间的微妙平衡，导致氧化应激，细胞外基质的组成改变和愈合受损。我们还将探讨这样一种假设，即尽管与影响伤口愈合的衰老相关的生理变化，但老年人伤口愈合受损患病率增加的主要原因是组织缺血。使用大鼠缺血性皮瓣模型，我们将：1）测试内源性抗氧化系统的失调导致缺血性伤口中活性氧净过量的假设，2）测试操纵缺血性伤口中的氧化还原平衡可以改善愈合的假设。3)检验氧化还原平衡影响基质金属蛋白酶活性的假设。使用的程序：Gould博士开发并验证的组织缺血大鼠模型（Wound Repair and Regeneration，2005）将用于测量年轻、中年和老年大鼠缺血性和非缺血性伤口中的氧化应激、内源性抗氧化剂、蛋白酶和蛋白酶抑制剂，并将这些因素与细胞外基质组成进行比较。将测试外源性抗氧化剂模拟物改变氧化还原平衡和改善伤口愈合的能力。特定细胞群在氧化还原稳态中的贡献将使用新的活组织测定来表征。为了进一步表征在氧化应激期间损害细胞功能的机制并验证这些机制在物种之间是一致的，来自不同年龄供体的原代人成纤维细胞将在缺氧、常氧和高氧条件下生长。利用内源性抗氧化剂的特异性抑制剂，将确定炎症介质、蛋白酶、基质产生和破坏的水平以及对细胞迁移的影响。重要性：我们的长期目标是阐明导致慢性伤口的细胞机制，以便开发合理的治疗方法来改善愈合或完全预防这些伤口。伤口愈合中发生的分子变化，特别是在老年人谁更常见的组织缺血，知之甚少。 公共卫生相关性： 对退伍军人医疗保健/相关性的潜在影响：920万退伍军人年龄在65岁或以上，占退伍军人总人口的38%。这个数字是美国总人口的三倍。因此，老年退伍军人的医疗保健是一个重大挑战。血液供应不良的伤口是最难治疗的伤口之一，并且正在成为老年人中日益严重的问题。通过了解缺血组织中伤口愈合受损的基本机制，我们将能够开发合理有效的治疗方法，从而在未来几年内降低退伍军人的成本和发病率。