THE PATHOGENESIS OF ADULT RESPIRATORY DISTRESS SYNDROME

该项目的总体假设是中性粒细胞隔离， 迁移和分泌是ARDS发展的关键事件。 在我们最初的建议中，我们建议诸如LPS或TNF的试剂 可以刺激中性粒细胞隔离，此外， 细胞随后刺激分泌弹性蛋白酶和O2-我们的工作， 日期表明，概述的事件确实发生在发展过程中 但没有明确区分那些重症患者， 有和没有患上这种综合症的人。 在本提案中，我们有 扩展了我们的假设，包括以下序列：LPS和其他 易患ARDS的病症的后遗症诱导IL-8的释放 和LTB 4，并导致中性粒细胞隔离，迁移和分泌 的）2和弹性蛋白酶。 我们进一步假设， 细胞因子和脂多糖改变了 中性粒细胞存在于正常受试者中，并导致 中性粒细胞亚群更可能被隔离， 加重肺损伤。 我们将在有ARDS风险和患有ARDS的患者中讨论该方案， 认识到类似的致病机制可能是共同的， 组 急性呼吸窘迫综合征（ARDS）患者肺内的神经元潴留， 使用自体111 In标记的中性粒细胞进行比较， 给予IL-1 r拮抗剂IL-1 ra、5-脂氧合酶 抑制剂齐留通和脂质体PGE 1，其可以直接调节 中性粒细胞功能。 正常人和患者的中性粒细胞将 根据流动性分成功能更同质的组， 细胞计数、粘弹性和体积标准。 LTB 4合成 体内，并在患者中进行合成的估计。 的影响 齐留通、IL-1 ra和lip-PGE 1对LTB 4代谢的影响将在 校正其对中性粒细胞功能异质性的影响。 的 氧化剂促进中性粒细胞隔离和 将使用MnSOD的输注来解决肺损伤。

The overall hypothesis of this project is that neutrophil sequestration, emigration and secretion are critical events in the development of ARDS. In our original proposal we suggested that agents such as LPS or TNF could stimulate neutrophil sequestration and, additionally, prime the cells for subsequent stimulation to secrete elastase and O2- Our work to date suggests that the outlined events do occur during the development of ARDS but no not clearly discriminate those critically ill patients at risk who do and do not develop the syndrome. In this proposal, we have expanded our hypothesis to include the following sequence: LPS and other sequelae of conditions that predispose to ARDS induce the release of IL-8 and LTB4, and lead to neutrophil sequestration, emigration and secretion of )2 and elastase. We further hypothesize that the presence of cytokines and LPS modifies the underlying functional heterogeneity of neutrophils present in normal subjects and results in the appearance of neutrophil subpopulations more likely to be sequestered that further enhance lung injury. We will address this scheme in patients at risk for, and with, ARDS, recognizing that similar pathogenic mechanisms may be common to both groups. Neutrophil retention in the lungs of patients with ARDS will be compared using autologous 111 In -labelled neutrophils before and after administration of the IL-1r antagonist, IL-1ra, the 5-lipoxygenase inhibitor Zileuton, and liposome PGE1 which may directly modulate neutrophil function. Neutrophils from normals and patients will be separated into more functionally homogenous groups based on flow cytometric, visco-elastic and volumetric criteria. LTB4 synthesis in vivo, and estimates of synthesis made in patients. The effect of Zileuton, IL-1ra and lip-PGE1 on LTB4 metabolism will be determined in correct with their effect on neutrophil functional heterogeneity. The potential for oxidants contributing to both neutrophil sequestration and lung injury will be addressed using the infusion of MnSOD.