INTERLEUKIN-1 INDUCED NEUTROPHIL MEDIATED ARDS

INTERLEUKIN-1 诱导的中性粒细胞介导的 ARDS

• 批准号: 6109915
• 负责人: JOHN E REPINE
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109915
• 关键词: adult respiratory distress syndrome; alveolar macrophages; antioxidants; biomarker; free radical oxygen; human tissue; hydrogen peroxide; inflammation; interleukin 1; interleukin 8; isolation perfusion; laboratory rat; leukotrienes; lung injury; neutrophil; protease inhibitor; vascular endothelium; vascular endothelium permeability; xanthine oxidase

For unknown reasons, patients wit ARDS have increased interleukin (IL-1), neutrophils, hydrogen peroxide (H202) and edema in their lungs and evidence of an altered lung and systemic oxidant-antioxidant balance. Our hypothesis is that toxic O2 radicals derived from xanthine oxidase (XO) and/or neutrophils contribute to lung leak in rats given IL-1 or ARDS patients. O2 radicals cause leak by peroxidizing lipids, oxidizing glutathione (GSH), inactivating antiprotease, and depleting vitamin E- processes which contribute to lung leak and further activate neutrophils. We propose that these events are associated with extracellular increases in SOD, catalase, XO, myeloperoxidase (MPO), GSSG and H2) which reflect and alter these processes. Our preliminary data supports this premise. Intratracheal IL-1 caused neutrophil accumulation and a neutrophil-dependent leak in lungs of intact rats which is associated with increased lung GSSG levels. Leak was decreased by treatment with DMSO, supercritical fluid aerosolized vitamin E, liposomal encapsulated PGE, or N-acetylcysteine-- in some cases even when these interventions are given after the IL-1 insult. IL-1 also caused leak and perfusate catalase increases in isolated lungs perfused with normal neutrophils but not heat-inactivated neutrophils which fail to make 02 radicals. In parallel, MnSOD, catalase and elastase-alpha1Pi complexes were increased in the blood of septic patients with ARDS compared to septic patients without ARDS. Our immediate specific aims are to determine the mechanisms responsible for lung leak in intact rats given IL-1 intratracheally or isolated IL-1 treated rat lungs perfused with neutrophils. Our investigations involve determination of the relationship of neutrophils, XO, oxidative injury and the appearance of extracellular markers in lungs treated with IL-1. Investigation also involves study of the effect of a carefully selected sequence of interventions that not only define these processes but also can potentially be used for treating ARDS patients. Parallel studies will evaluate neutrophils and serum from patients with and at risk for ARDS as a function of ARDS progression and intervention. The significance of these studies is (1) to improve understanding of fundamental mechanisms responsible for acute lung injury, (2) to gain new information regarding the predictive and functional value of extracellular markers and (3) to identify and define interventions which might be useful in treating or preventing ARDS.

由于未知的原因，患者的白介素（IL-1）增加了， 中性粒细胞，过氧化氢（H202）和肺中的水肿， 肺和全身氧化剂抗氧化剂平衡改变的证据。 我们的假设是衍生自黄嘌呤氧化酶的有毒O2自由基 （XO）和/或中性粒细胞有助于给定IL-1或 ARDS患者。 O2自由基通过过氧化脂质引起泄漏，氧化 谷胱甘肽（GSH），抗抗原蛋白并灭活维生素E- 导致肺泄漏并进一步激活嗜中性粒细胞的过程。 我们建议这些事件与细胞外增加有关 在SOD，过氧化氢酶，XO，骨髓过氧化物酶（MPO），GSSG和H2中反射 并改变这些过程。 我们的初步数据支持此前提。 气管内IL-1引起 中性粒细胞的积累和中性粒细胞依赖性肺 完整的大鼠与肺GSSG水平升高有关。 泄露 通过用DMSO，超临界液雾化而减少 维生素E，脂质体封装PGE或N-乙酰半胱氨酸 - 即使在IL-1侮辱后给予这些干预措施，也会给予这些干预措施。 IL-1 还会导致泄漏和灌注量过高酶增加孤立的肺 用正常的嗜中性粒细胞灌注，但没有热灭活的中性粒细胞 无法制作02个激进分子。 并行，MNSOD，过氧化氢酶和 败血症的血液中的弹性酶-alpha1pi复合物增加 与没有ARDS的化粪池患者相比，ARDS患者。 我们的直接具体目的是确定负责的机制 为IL-1的气管内或分离的IL-1，用于完整大鼠的肺泄漏 用嗜中性粒细胞灌注的大鼠肺处理。 我们的调查涉及 确定中性粒细胞，XO，氧化损伤的关系 以及用IL-1处理的肺部细胞外标记的出现。 调查还涉及研究精心选择的效果 干预措施的顺序不仅定义了这些过程，还定义 可以可能用于治疗ARDS患者。 平行研究 将评估有和有风险的患者的中性粒细胞和血清 ARDS是ARDS进展和干预的函数。 这些研究的意义是（1）提高对 负责急性肺损伤的基本机制，（2）获得新的 有关预测和功能价值的信息 细胞外标记和（3）以识别和定义干预措施 可能对治疗或预防ARD有用。