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.

由于未知原因，ARDS 患者白细胞介素 (IL-1) 升高， 中性粒细胞、过氧化氢 (H2O2) 和肺部水肿 肺部和全身氧化-抗氧化平衡改变的证据。 我们的假设是有毒的 O2 自由基源自黄嘌呤氧化酶 (XO)和/或中性粒细胞导致给予IL-1或IL-1的大鼠肺渗漏 急性呼吸窘迫综合征患者。 O2 自由基通过过氧化脂质、氧化 谷胱甘肽 (GSH)，使抗蛋白酶失活，并消耗维生素 E- 导致肺渗漏并进一步激活中性粒细胞的过程。 我们认为这些事件与细胞外增加有关 SOD、过氧化氢酶、XO、髓过氧化物酶 (MPO)、GSSG 和 H2），反映了 并改变这些过程。 我们的初步数据支持这一前提。 气管内IL-1引起 肺部中性粒细胞积聚和中性粒细胞依赖性渗漏 完整的大鼠，这与肺 GSSG 水平增加有关。 泄露 通过 DMSO、超临界流体雾化处理降低 维生素 E、脂质体包裹的 PGE 或 N-乙酰半胱氨酸——在某些情况下 即使在 IL-1 损伤后进行这些干预措施。白细胞介素1 还导致离体肺中渗漏和灌注液过氧化氢酶增加 灌注正常中性粒细胞，但不灌注热失活的中性粒细胞 无法生成 02 部首。 同时，MnSOD、过氧化氢酶和 脓毒症患者血液中弹性蛋白酶-α1Pi复合物增加 患有 ARDS 的患者与没有 ARDS 的脓毒症患者进行比较。 我们当前的具体目标是确定负责的机制 用于气管内给予 IL-1 或分离 IL-1 的完整大鼠的肺漏 用中性粒细胞灌注处理过的大鼠肺。 我们的调查涉及 中性粒细胞、XO、氧化损伤关系的测定 以及用 IL-1 处理的肺中细胞外标记物的出现。 调查还包括研究精心挑选的效果 干预措施的顺序不仅定义了这些过程，而且 可以潜在地用于治疗 ARDS 患者。 平行研究 将评估患有或有风险的患者的中性粒细胞和血清 ARDS 作为 ARDS 进展和干预的函数。 这些研究的意义在于（1）增进对 造成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 细胞外标志物和（3）识别和定义干预措施 可能有助于治疗或预防 ARDS。