Tissue oxygenation and wound angiogenesis

描述（由申请方提供）：慢性伤口的病因通常是多因素的，其中缺氧是一个常见因素。涉及缺氧伤口的临床病症包括外周血管病变（糖尿病、动脉硬化等），术后恢复和动脉缺氧（例如肺纤维化或肺炎、交感神经痛反应、体温过低、大量失血、紫绀性心脏病、高海拔）。该提案解决了O2在此类病例伤口愈合中的重要性。该建议有两个方面：理解伤口中的氧敏感机制，以及开发伤口氧合的方法。第一次，高度重要的血红蛋白为基础的HBOC（“人造血液”）技术正在研究伤口氧合。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的。虽然缺氧急性触发血管生成因子和反应的表达，但长期缺氧不能维持新的功能性脉管系统的形成，从而导致伤口慢性化。纠正伤口缺氧支持愈合。目的1和2基于小鼠缺氧会损害全层真皮伤口愈合的观察结果。纠正缺氧恢复伤口闭合目的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制剂的影响：i.建立组织氧合对伤口闭合的影响; ii.检查组织氧合对在早期炎症阶段中用于伤口血管生成的制剂的影响; iii.测试缺氧诱导因子（HIF）在缺氧条件下伤口血管生成中的作用。AIM 2.确定组织氧合状态在后期组织重塑阶段影响伤口血管生成的机制：i.确定缺氧诱导的真皮伤口TGF β 1抑制的意义; ii.研究在有限的O2条件下低伤口部位NO产生的作用。AIM 3.在缺血性伤口的临床前猪模型中测试伤口的氧合是否影响全层真皮伤口愈合：测试O2的局部应用（基于气体和基于HBOC的方法）是否校正全层伤口缺氧; ii.确定氧合是否加速伤口闭合; iii.确定伤口缺氧的纠正是否促进血管生成和血流。

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.