Hyperbaric Oxygenation May Increase Lung Injury

描述（由申请人提供）：高压氧治疗（HBOT）是基础生物医学研究人员和补充和替代医学（CAM）从业者感兴趣的。HBOT适用于多种疾病，其症状是由靶组织缺氧引起的。由于对潜在的生理学缺乏了解，并且尚未仔细评估潜在的危险，因此美国医学界不接受它作为一种治疗方法。需要进行广泛的临床前研究，以克服目前对HBOT的偏见，并确定其局限性。这项建议的中心目标是了解HBOT的有益影响的机制，并确定其潜在的危险。我们最近建立了低氧驱动和A2 A和A2 B腺苷受体（A2 AR/A2 BR）介导的途径在抑制过度活跃的炎症细胞和保护缺氧炎症区域的正常组织中的关键作用。我们推测，在HBOT过程中通过氧气消除这种机制可以解释HBOT在清除感染中通过“去抑制”免疫细胞的有益作用。我们还担心HBOT对这种保护机制的削弱可能会导致炎症组织损伤的意外加剧。我们计划在HBOT治疗的野生型小鼠和在不同的肺部炎症模型中A2 AR和/或A2 BR基因完全和组织特异性缺失的独特小鼠的研究中测试我们的假设。我们的具体目标#1和2是在吸入和静脉内诱导的小鼠肺损伤模型的研究中测试HBOT是否加剧肺部炎症，而在目标#3中，我们将测试用A2 AR激动剂的补偿治疗是否会预防HBOT引起的炎性肺损伤恶化，以获得HBOT用于CAM和其他疗法中的其他适应症的潜在益处。

DESCRIPTION (provided by applicant): Hyperbaric Oxygen therapy (HBOT) is of interest to basic biomedical researchers and to practitioners of complementary and alternative medicine (CAM). HBOT is applied to a wide variety of diseases with symptoms caused by a lack of oxygen in the target tissues. It is not accepted as a treatment by the US medical community due to the lack of understanding of the underlying physiology and yet to be carefully evaluated potential dangers. Extensive pre-clinical studies are required to overcome the current bias towards HBOT and to determine its limitations. The central goal of this proposal is to understand the mechanisms of beneficial effects of HBOT and to identify its potential dangers. We recently established the critical role of the hypoxia-driven and A2A and A2B adenosine receptor (A2AR/A2BR)-mediated pathway in inhibition of overactive inflammatory cells and protection of normal tissues in hypoxic inflamed areas. We hypothesize that the elimination of this mechanism by oxygen during HBOT may explain the beneficial effects of HBOT in clearing infections by "de-inhibited" immunocytes. We are also concerned that the weakening of this protective mechanism by HBOT may lead to an unintended exacerbation of inflammatory tissue damage. We plan to test our hypothesis in studies of HBOT-treated wild type mice and of unique mice with total and tissue-specific deletion of A2AR and/or A2BR genes in different models of lung inflammation. Our specific aims #1 and 2 are to test whether HBOT exacerbates lung inflammation in studies of inhalative and intravenously induced models of lung injury in mice, while in Aim #3 we will test whether compensatory treatment with A2AR agonist will prevent the inflammatory lung injury exacerbation by HBOT in order to gain potential benefits of HBOT for other indications in CAM and other therapies.