REGULATION OF INFLAMMATORY LIPIDS IN ACUTE LUNG INJURY

成人呼吸窘迫综合征（ARDS）是一种严重的急性肺损伤， 经常是致命的伤害。许多证据表明， 该综合征的共同特征是不受调节的炎症和条件 其中存在全身性炎症，例如脓毒症，是常见 前体治疗策略，以恢复调节的 炎症反应可能有效地防止了 综合征或逆转既定的疾病。动物和人类的研究 血小板活化因子（PAF）是一种磷脂， 有效的促炎作用，作为脓毒症的重要介质， 肺损伤在上一个资助期，我们分离了一个编码 PAF乙酰水解酶（AH）是降解PAF的酶， 磷脂此外，我们发现重组酶阻断了 动物模型中的炎症，包括一种致命的败血症。这些 和其他研究结果支持临床试验的启动，其中 我们正在参与，以测试重组PAF-AH作为干预， 防止从高危状态发展为ARDS。在这个项目中，我们 将使用动物模型，包括基因工程小鼠，来测试 假设PAF和密切相关的化合物在共同的途径上 急性肺损伤在上一个融资期，我们发现， 结构上类似于PAF的磷脂家族可以通过以下方式产生： 非酶氧化，这可能发生在ARDS中。这些 化合物，如PAF，支持炎症反应。PAF样生物活性 存在于ARDS患者的支气管肺泡液中，我们 发现表面活性剂可以被氧化成具有PAF样的脂质 生物活性因此，我们将测试假设， PAF样生物活性在严重炎症中的作用是由氧化 磷脂而不是真正的PAF。这可能会导致额外的 治疗方法，如果氧化剂介导的过程是突出的。 最后，PAF可诱导细胞因子和趋化因子的合成， 主动脉血管平滑肌细胞增殖。因此， 该项目将测试PAF或氧化磷脂是否介导慢性 ARDS幸存者的后遗症，如果PAH-AH可以防止这种 事件

The Adult Respiratory Distress Syndrome (ARDS) is severe, acute lung injury that is frequently lethal. Many lines of evidence suggest that a common feature of the syndrome is unregulated inflammation and conditions in which there is systemic inflammation, such as sepsis, are common precursors. Therapeutic strategies to restore the regulation of the inflammatory response might be effective in either preventing the onset of the syndrome or reversing established disease. Studies in animals and man have implicated platelet-activating factor (PAF), a phospholipid with potent pro-inflammatory actions, as an important mediator in sepsis and lung injury. In the previous funding period, we isolated a cDNA encoding PAF acetylhydrolase (AH), the enzyme that degrades PAF and closely related phospholipids. In addition, we have found that recombinant enzyme blocks the inflammation in animal models, including one of lethal sepsis. These and other findings supported the initiation of clinical trials, in which we are participating, to test recombinant PAF-AH as an intervention to prevent progression from at-risk conditions to ARDS. In this project we will use animal models, including genetically engineered mice, to test the hypothesis that PAF and closely related compounds are on a common pathway to acute lung injury. In the previous funding period we found that a family of phospholipids structurally similar to PAF can be generated by non-enzymatic oxidation, which is likely to occur in ARDS. These compounds, like PAF, support inflammatory responses. PAF-like bioactivity is present in bronchoalveolar fluid of patients with ARDS, and we discovered that surfactant could be oxidized to a lipid with PAF-like bioactivity. Thus, we will test the hypotheses that a substantial fraction of PAF-like bioactivity in severe inflammation results from oxidized phospholipids rather than authentic PAF. This might lead to additional therapeutic approaches if the oxidant-mediated processes are prominent. Finally, PAF can induce cytokine and chemokine synthesis, and stimulate the proliferation of aortic vascular smooth muscle cells. Thus, this project will test whether PAF, or oxidized phospholipids, mediate chronic sequelae in survivors of ARDS, and if PAH-AH can protect against such events.