Tissue oxygenation and wound angiogenesis

组织氧合和伤口血管生成

• 批准号: 7468445
• 负责人: Chandan K Sen
• 金额: $ 26.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468445
• 关键词: Abbreviations; Address; Altitude; Angiogenic Factor; Arteriosclerosis; Blood Substitutes; Blood flow; Brain Hypoxia-Ischemia; Cell Respiration; Chronic; Clinical; Closure; Condition; Data; Dermal; Enabling Factors; Etiology; Experimental Models; Family suidae; Gases; Genes; Healed; Heart Diseases; Hemoglobin; Hemorrhage; Histology; Hypoxia; Hypoxia Inducible Factor; Impaired wound healing; Impairment; Inflammatory; Ischemia; Lasers; Measures; Modeling; Mus; Myofibroblast; Natural regeneration; Numbers; Outcome; Oxygen; Oxygen saturation measurement; Pain; Paper; Peripheral; Phase; Pneumonia; Postoperative Period; Preparation; Process; Production; Pulmonary Fibrosis; Recovery; Reporting; Research Personnel; Rest; Role; Site; Skin; Sus scrofa; System; Technology; Testing; Text; Thick; Time; Tissues; Upper arm; Viral; Viral Vector; Wound Healing; angiogenesis; base; design; diabetic; experience; healing; improved; in vivo; innovation; insight; mouse model; natural hypothermia; novel; pre-clinical; programs; response; restoration; tissue oxygenation; tool; vector; wound

DESCRIPTION (provided by applicant): The etiology of chronic wounds is generally multi-factorial of which hypoxia is a common factor. Clinical conditions involving hypoxic wound include peripheral vasculopathy (diabetics, arteriosclerosis, etc.), post- operative recovery, and arterial hypoxia (e.g. pulmonary fibrosis or pneumonia, sympathetic pain response, hypothermia, major blood loss, cyanotic heart disease, high altitude). This proposal addresses the significance of O2 in wound healing of such cases. The proposal has two facets: understanding oxygen- sensitive mechanisms in the wound, and developing approaches for wound oxygenation. For the first time, the highly significant hemoglobin-based HBOC ("artificial blood") technology is being studied for wound oxygenation. The central hypothesis is that wound oxygenation is a key determinant of wound angiogenesis. Chronic ischemic wounds are typically hypoxic. While hypoxia acutely triggers the expression of angiogenic factors and responses, long-term hypoxia cannot sustain the formation of new functional vasculature resulting in wound chronicity. Correction of wound hypoxia supports healing. Aims 1 and 2 rest on the observation that hypoxia in mice impairs the healing of full thickness dermal wounds. Correction of hypoxia, restored wound closure. Aim 3 is based on similar observations in a pre-clinical swine model of ischemic wound. The following three aims are proposed: AIM 1. Characterize the effects of tissue oxygenation on the preparation for wound angiogenesis: i. Establish the effects of tissue oxygenation on wound closure; ii. Examine the effects of tissue oxygenation on the preparation for wound angiogenesis in the early inflammatory phase; iii. Test the role of hypoxia-inducible factor (HIF) in wound angiogenesis under conditions of hypoxia. AIM 2. Determine the mechanisms by which the state of tissue oxygenation influences wound angiogenesis in the late tissue-remodeling phase: i. Determine the significance of hypoxia-induced inhibition of dermal wound TGFbl; ii. Investigate the role of low wound-site NO production under conditions of limited O2. AIM 3. Test whether oxygenation of wounds influences full-thickness dermal wound healing in a pre-clinical swine model of ischemic wound: i. Test whether local application of O2 (gas-based and HBOC- based approaches) corrects full-thickness wound hypoxia; ii. Determine whether oxygenation accelerates wound closure; iii. Determine if correction of wound hypoxia facilitates angiogenesis and blood flow.

描述（由申请人提供）：慢性伤口的病因通常是多因素的多因素，缺氧是一个常见因素。涉及低氧伤口的临床疾病包括外周血管病（糖尿病患者，动脉粥样硬化等），手术后康复和动脉缺氧（例如肺纤维化或肺炎，交感神经疼痛反应，体温过低，主要失血，cyanotic Heart疾病，高高度）。该提案解决了O2在此类病例的伤口愈合中的重要性。该提案有两个方面：了解伤口中的氧气敏感机制，以及开发伤口氧合的方法。第一次，正在研究基于血红蛋白的HBOC（“人造血”）技术以进行伤口氧合。中心假设是伤口氧合是伤口血管生成的关键决定因素。慢性缺血性伤口通常是缺氧。低氧急性触发了血管生成因素和反应的表达，但长期缺氧无法维持新功能性脉管系统的形成，导致伤口慢性。伤口缺氧的矫正支持愈合。目的1和2基于观察到小鼠缺氧会损害全厚性皮肤伤口的愈合。纠正缺氧，恢复的伤口闭合。 AIM 3基于缺血性伤口的临床前猪模型中的类似观察结果。提出了以下三个目标：目标1。表征组织氧合对伤口血管生成的准备的影响：i。建立组织氧合对伤口闭合的影响； ii。检查组织氧合对早期炎症阶段伤口血管生成的准备的影响； iii。在缺氧条件下测试缺氧诱导因子（HIF）在伤口血管生成中的作用。目标2。确定组织氧合状态在组织后期重塑阶段影响伤口血管生成的机制：i。确定缺氧引起的皮肤伤口TGFBL的抑制作用； ii。研究低伤口站点在有限的O2条件下无生产的作用。 AIM 3。测试伤口的氧合是否会影响全厚性皮肤伤口愈合，这是缺血性伤口的临床前猪模型：i。测试局部应用O2（基于气体和基于HBOC的方法）是否纠正全厚性伤口缺氧； ii。确定氧合是否会加速伤口闭合； iii。确定伤口缺氧的纠正是否有助于血管生成和血流。