Topical Modulation of Burn Wound Healing

描述（由申请人提供）：我们的中心假设是，对热损伤的炎症反应导致内源性蛋白酶及其抑制剂失衡，导致愈合受损。在这项合作努力中，我们提出，可以通过使用局部伤口敷料来改善烧伤伤口愈合，这些敷料能够影响参与炎症反应的关键介质。治疗剂IMS-70已被证明具有抑制嗜中性粒细胞衍生蛋白酶的内在能力，将作为我们伤口治疗的愈合组分进行评价。我们预测，大多数的改善将发生在停滞区。我们的假设将通过以下具体目标进行检验： 具体目标1）：IMS-70及其衍生物的配制和体外筛选 IMS-70将进行化学修饰，以纳入抗生素和MMP抑制剂，强力霉素;活性氧清除剂，谷胱甘肽;抗菌铈离子和营养精氨酸。将进行体外筛选以测试这些衍生物抑制蛋白酶如嗜中性粒细胞衍生的弹性蛋白酶、组织蛋白酶G、MMP-8和MMP-9以及嗜中性粒细胞衍生的髓过氧化物酶的能力。 具体目标2）：IMS-70和衍生物的体内测试。 IMS-70衍生物将混合到CMC无定形水凝胶载体中，并应用于大鼠的烧伤伤口。该模型生成由代表停滞区的非烧伤间隙分隔的全层烧伤区域。将通过比较组织学、蛋白酶活性和炎症标志物与仅接受水凝胶载体的对照组来测试敷料的有效性。 成功完成本提案中概述的具体目标将提供必要的数据，以优化用于较大表面积烧伤的局部治疗，可能限制导致烧伤创面脓毒症、烧伤创面转化和恢复时间延长的全身效应。公共卫生相关性项目叙述：热损伤引发复杂的炎症反应，可能导致未烧伤组织的广泛损伤。在本提案中，我们描述了旨在限制炎症反应从而减少烧伤伤口损伤程度的新型局部治疗的开发和测试。这些基本机制也适用于化学烧伤和辐射诱导的损伤，以及其他皮肤炎性疾病。

DESCRIPTION (provided by applicant): Our central hypothesis is that the inflammatory response to thermal injury results in an imbalance of endogenous proteases and their inhibitors resulting in impaired healing. In this collaborative effort, we propose that burn wound healing can be improved through the use of topical wound dressings with the capacity to affect key mediators involved in the inflammatory response. The therapeutic agent IMS-70, which has demonstrated an intrinsic ability to inhibit neutrophil-derived proteases, will be evaluated as a healing component of our wound treatment(s). We predict that the majority of improvement will occur in the zone of stasis. Our hypothesis will be tested with the following specific aims: Specific Aim 1): Formulation and in vitro screening of IMS-70 & Derivatives IMS-70 will be chemically modified to incorporate the antibiotic and MMP inhibitor, doxycycline; the reactive oxygen species scavenger, glutathione; the antimicrobial cerium ion, and the nutrient arginine. In vitro screening will be performed to test the ability of these derivatives to inhibit proteases such as neutrophil-derived elastase, cathepsin G, MMP-8 and MMP-9 and neutrophil- derived myeloperoxidase. Specific Aim 2): In vivo testing of IMS-70 & Derivatives. The IMS-70 derivatives will be blended into a CMC amorphous hydrogel carrier and applied to a burn wound in the rat. This model generates areas of full- thickness burn separated by non-burned interspaces representing the zone of stasis. The efficacy of the dressings will be tested by comparing histology, protease activity, and inflammatory markers to a control group receiving only the hydrogel carrier. Successful completion of the specific aims outlined in this proposal will provide the necessary data to optimize topical therapies for use in larger surface area burns, potentially limiting the systemic effects that result in burn wound sepsis, burn wound conversion, and prolonged recovery. PUBLIC HEALTH RELEVANCE Project Narrative: Thermal injury triggers a complex inflammatory response that can result in extensive damage to the unburned tissues. In this proposal we describe the development and testing of novel topical therapies designed to limit the inflammatory response and thereby reduce the extent of burn wound injury. These basic mechanisms will also apply to chemical burns and radiation induced injury, as well as other inflammatory diseases of the skin.