Tissue oxygenation and wound angiogenesis

描述(申请人提供)：慢性创面的病因通常是多因素的，其中缺氧是一个共同的因素。涉及缺氧创面的临床情况包括外周血管病变(糖尿病患者、动脉硬化等)、术后恢复和动脉缺氧(例如肺纤维化或肺炎、交感神经疼痛反应、体温过低、大量失血、青紫型心脏病、高原)。这项建议阐述了氧气在这类病例的伤口愈合中的重要性。该提议包括两个方面：了解伤口中的氧敏感机制，以及开发伤口氧合的方法。基于高度重要的基于血红蛋白的HBOC(“人造血”)技术首次被用于伤口氧合的研究。中心假设是创面氧合是创面血管生成的关键决定因素。慢性缺血性伤口通常是低氧的。虽然低氧强烈地触发了血管生成因子和反应的表达，但长期低氧不能维持新的功能性血管的形成，从而导致创面的慢性化。纠正伤口缺氧有助于愈合。目的1和2基于观察到小鼠的低氧损害了全层真皮伤口的愈合。纠正缺氧，恢复伤口闭合。AIM 3是基于临床前猪缺血创面模型的类似观察。目的1.研究组织氧合对创面血管生成准备的影响：i.建立组织氧合对创面闭合的影响；检测组织氧合对早期炎症阶段创面血管生成准备的影响；检测缺氧条件下缺氧诱导因子(HIF)在创面血管生成中的作用。目的2.确定组织氧合状态在组织重塑晚期影响创面血管生成的机制：1.确定低氧抑制真皮创面TGFb1的意义；研究在低氧条件下伤口处低NO产生的作用。目的3.在临床前的猪缺血创面模型中，测试创面氧合是否影响全层真皮创面愈合：i.局部应用O2(基于气体和基于HBOC的方法)是否纠正全层创面缺氧；确定氧合是否加速伤口闭合；确定纠正伤口缺氧是否促进血管生成和血液流动。

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.