THE PATHOGENESIS OF ADULT RESPIRATORY DISTRESS SYNDROME

这个项目的总体假设是中性粒细胞隔离， 移居和分泌是ARDS发展过程中的关键事件。 在我们最初的提案中，我们建议像脂多糖或肿瘤坏死因子这样的试剂 可以刺激中性粒细胞的隔离，此外，还可以启动 用于随后刺激分泌弹性蛋白酶和O2的细胞-我们的工作是 日期表明概述的事件确实发生在开发过程中 但没有明确区分那些危重病人 谁有和谁没有发展成综合症的风险。在这项提案中，我们有 将我们的假设扩展到包括以下序列：LP和其他 易患ARDS的条件的后遗症导致IL-8的释放 和LTB4，并导致中性粒细胞隔离、迁移和分泌 2和弹性淀粉酶。我们进一步假设， 细胞因子和内毒素改变血管内皮细胞潜在的功能异质性 中性粒细胞存在于正常受试者并导致出现 中性粒细胞亚群更有可能被进一步隔离 加强肺损伤。 我们将在有ARDS风险的患者中解决这一方案， 认识到相似的致病机制可能对两者都是共同的 组。ARDS患者肺部中性粒细胞滞留 111In标记的中性粒细胞使用前后的比较 5-脂氧合酶IL-1R拮抗剂IL-1ra的应用 抑制剂齐留通和可直接调节的脂质体PGE1 中性粒细胞功能。正常人和病人的中性粒细胞 根据流量划分为功能更同质的组 细胞学、粘弹性和体积标准。LTB4的合成 活体，以及对患者体内合成的估计。的影响 齐留通、IL-1ra和Lip-PGE1对LTB4代谢的影响将在 更正了它们对中性粒细胞功能异质性的影响。这个 氧化剂对中性粒细胞隔离和 肺损伤将通过输注MnSOD来解决。

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.