Tissue oxygenation and wound angiogenesis

描述（由申请人提供）：慢性伤口的病因通常是多因素的，其中缺氧是一个常见的因素。低氧伤口的临床情况包括周围血管病变（糖尿病、动脉硬化等）、术后恢复、动脉缺氧（如肺纤维化或肺炎、交感疼痛反应、体温过低、大出血、青紫性心脏病、高原）。这一建议解决了O2在这种情况下伤口愈合的意义。该建议有两个方面：了解伤口中的氧敏感机制，并发展伤口氧合方法。基于血红蛋白的HBOC（“人造血液”）技术首次被用于伤口氧合研究。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的表达和反应，但长期缺氧不能维持新功能血管的形成，导致伤口慢性。纠正伤口缺氧有助于愈合。目的1和目的2基于小鼠缺氧损伤真皮全层创面愈合的观察。纠正缺氧，恢复伤口闭合。目的3是基于临床前猪缺血性伤口模型的类似观察。提出以下三个目标：目标1。描述组织氧合对创面血管生成准备的影响：1 .建立组织氧合对创面闭合的影响；2。探讨炎症早期组织氧合对创面血管生成准备的影响；3。检测缺氧诱导因子（HIF）在缺氧条件下创面血管生成中的作用。目标2。确定组织重构后期组织氧合状态影响创面血管生成的机制：1 .确定缺氧诱导的真皮创面TGFbl抑制的意义；2。探讨在缺氧条件下低创口NO生成的作用。目标3。在临床前猪缺血性创面模型中测试伤口氧合是否影响全层皮肤创面愈合：i.测试局部应用O2（基于气体和基于HBOC的方法）是否纠正全层创面缺氧；2。判断氧合是否加速伤口愈合；3。确定伤口缺氧的纠正是否有助于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.