INFLAMMATORY MEDIATORS

炎症介质

• 批准号: 6318362
• 负责人: CHARLES PALMER
• 金额: $ 15.82万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6318362
• 关键词: brain injury; brain metabolism; cerebral ischemia /hypoxia; cytokine receptors; histopathology; immature animal; inflammation; interleukin 1; iron metabolism; laboratory mouse; laboratory rat; lipid metabolism; lipopolysaccharides; magnetic resonance imaging; microglia; neutrophil; nitric oxide; nuclear factor kappa beta; nuclear magnetic resonance spectroscopy; perinatal; peroxidation; tumor necrosis factor alpha

The objective of this project is to define the key mechanisms leading to hypoxic-ischemic brain injury in the human newborn. Clinical and experimental studies show that after an initial recovery in brain energy metabolism there is a secondary decline that may extend for months What are the key mechanisms responsible for early and late brain injury and can any aspect of the injury process by reduced by therapeutic intervention are clinical priorities addressed in this proposal. We will continue to study the immature rat model of cerebral hypoxia-ischemia. The central focus is to determine how inflammation before hypoxia-ischemia as well as inflammation induced by the consequences of brain injury contribute to progressive brain damage. As brain injury in the neonate is strongly associated with exposure to infection in utero, we will mimic the neuro- inflammation effects of systemic infection by giving immature rates lipopolysaccharide (LPS). Evaluations will include systemic and cerebral analyses of giving immature rats lipopolysaccharide (LPS). Evaluation will include systemic and cerebral analyses of giving immature rats lipopolysaccharide (LPS). Evaluations will include systemic and cerebral analyses of inflammatory cells (neutrophils and microglia), cytokines, nuclear transcription factor NF-kappaB activation, brain lipid peroxidation, and disturbances in brain iron metabolism. Mice lacking the receptor for IL-1 will aid in defining IL-1's role in the response to LPS as will anti-cytokine treatment. Specific Aims include: Aim 1: To establish the systemic and cerebral inflammatory responses of immature rats to infections of LPS. Aim 2: To expose immature rats to a combination of LPS and cerebral hypoxia-ischemia to determine whether or not the combined stress accentuates hypoxic-ischemic brain damage in the immature rat. Aim 3: To investigate how nitric oxide contributes to Poly (ADP-ribose)polymerase (PARP) activation and delayed brain energy failure following hypoxia-ischemia and LPS administration in the immature rat. Aim 4: To characterize the chronic neuropathologic alterations which result from cerebral hypoxia-ischemia in the immature rat. Our investigations also will include in vivo sequential MR imaging ant 31P NMR spectroscopy to measure the progression of cerebral atrophy and energy failure in the same rats over the first year of recovery. We will use pharmacologic agents in vivo to test the contribution of key injury mechanisms, including drugs directed at cytok9ines, free radicals, iron nitric oxide, and PARP. We will use biochemical, histologic, and neuropathologic techniques to determine if LPS primes the brain for greater ischemic injury and if a chronic damaging inflammatory process is induced by the primary insult.

该项目的目标是确定导致人类新生儿缺氧缺血性脑损伤的关键机制。临床和实验研究表明，脑能量代谢初步恢复后，会出现继发性下降，可能持续数月。造成早期和晚期脑损伤的关键机制是什么？可以通过治疗干预来减少损伤过程的任何方面吗？该提案中涉及的临床优先事项。我们将继续研究未成熟大鼠脑缺氧缺血模型。中心重点是确定缺氧缺血前的炎症以及脑损伤后果引起的炎症如何导致进行性脑损伤。由于新生儿的脑损伤与子宫内感染密切相关，因此我们将通过给予未成熟率脂多糖（LPS）来模拟全身感染的神经炎症效应。评估将包括对未成熟大鼠给予脂多糖（LPS）的全身和大脑分析。评估将包括对未成熟大鼠给予脂多糖（LPS）的全身和大脑分析。评估将包括炎症细胞（中性粒细胞和小胶质细胞）、细胞因子、核转录因子 NF-κB 激活、脑脂质过氧化和脑铁代谢紊乱的系统和脑分析。缺乏 IL-1 受体的小鼠将有助于确定 IL-1 在 LPS 反应中的作用，以及抗细胞因子治疗。具体目标包括： 目标 1：建立未成熟大鼠对 LPS 感染的全身和脑部炎症反应。目标 2：将未成熟大鼠暴露于 LPS 和脑缺氧缺血的组合中，以确定联合应激是否会加重未成熟大鼠的缺氧缺血性脑损伤。目标 3：研究一氧化氮如何促进未成熟大鼠缺氧缺血和 LPS 给药后聚（ADP-核糖）聚合酶（PARP）激活和延迟脑能量衰竭。目标 4：表征未成熟大鼠脑缺氧缺血引起的慢性神经病理学改变。我们的研究还将包括体内连续 MR 成像和 31P NMR 波谱，以测量同一只大鼠在恢复的第一年中脑萎缩和能量衰竭的进展情况。我们将使用体内药物来测试关键损伤机制的贡献，包括针对细胞因子、自由基、一氧化氮铁和 PARP 的药物。我们将使用生化、组织学和神经病理学技术来确定脂多糖是否会导致大脑发生更大的缺血性损伤，以及初级损伤是否会诱发慢性破坏性炎症过程。