INTERCELLULAR ADHESION MOLECULE 1 AND ACUTE LUNG INJURY

细胞间粘附分子 1 与急性肺损伤

• 批准号: 6109742
• 负责人: LING-YI L CHANG
• 金额: $ 21.31万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109742
• 关键词: cell adhesion molecules; cell migration; cellular pathology; cytokine; genetically modified animals; hyperoxia; inflammation; laboratory mouse; laboratory rat; lung alveolus; lung injury; messenger RNA; neutrophil; respiratory epithelium; tissue /cell culture; western blottings

The objectives of this research proposal are to first, study PMN migration across the alveolar septum, especially PMN migration from alveolar air spaces to the interstitium and second, to define the role of lung endothelial and epithelial ICAM-1 in regulating PMN migration in inflamed lungs and its consequent effects on long injury. The lung contains a large alveolar surface area that is exposed constantly to inflammatory stimuli as well as a large marginated pool of neutrophils. The regulation of neutrophil migration in the lung is critical for maintaining the integrity of the delicate alveolar septum. The alveolar epithelium has an extraordinary high expression of ICAM-1, an adhesion molecule known to effect stable binding of PMNs to cell surfaces and thought to play an important role in regulating PMN extravasation into inflamed tissues. The expression of ICAM-1 on lung epithelial cells in situ can be modified by hyperoxic exposure and proinflammatory cytokines. We hypothesize that alveolar epithelial surface ICAM-1 is involved in regulating PMN migration in the lung. There are six specific aims in this research proposal. 1. Study the role of epithelial ICAM-1 on PMN trans-epithelial migration in an in vitro epithelial culture system. 2. Demonstrate migration of PMNs from alveolar air spaces into the interstitium under physiological conditions and study the subsequent clearance of interstitial PMNs. 3. Define the effects of selected proinflammatory cytokines on ICAM-1 of specific lung cells. 4. Define the role of iCAM-1 in regulating neutrophil clearance from the alveolar surface in mouse lungs that have either a normal or modified distribution pattern of iCAM-1. 5. Define the time course of changes in ICAM-1 expression and the corresponding course of neutrophil invasion in the development of pulmonary inflammation. 6. Test the effectiveness of anti-ICAM-1 antibodies in preventing neutrophil infiltration and protect against lung injury. Successful completion of these aims will enhance our understanding of the mechanisms controlling the development of neutrophil dependent lung injury during inflammation.

本研究提案的目标是首先研究 PMN 迁移 穿过肺泡间隔，尤其是 PMN 从肺泡空气中迁移 其次，定义肺的作用 内皮和上皮 ICAM-1 在调节炎症中 PMN 迁移中的作用 肺部及其对长期损伤的后续影响。 肺里含有大量的 肺泡表面积不断暴露于炎症刺激下 以及大量边缘化的中性粒细胞。 的监管 中性粒细胞在肺部的迁移对于维持完整性至关重要 脆弱的肺泡间隔。 肺泡上皮具有 ICAM-1 的异常高表达，这是一种已知的粘附分子 影响 PMN 与细胞表面的稳定结合，并被认为发挥着 在调节 PMN 外渗至发炎组织中发挥重要作用。 这 ICAM-1在肺上皮细胞上的原位表达可以通过以下方式修饰： 高氧暴露和促炎细胞因子。 我们假设 肺泡上皮表面ICAM-1参与调节PMN迁移 在肺里。 本研究提案有六个具体目标。 1. 研究上皮 ICAM-1 对 PMN 跨上皮迁移的作用 体外上皮培养系统。 2. 证明 PMN 的迁移 生理条件下肺泡空气进入间质 并研究间质中性粒细胞的后续清除。 3. 定义 选定的促炎细胞因子对特定肺 ICAM-1 的影响 细胞。 4. 定义iCAM-1在调节中性粒细胞清除中的作用 来自具有正常或正常状态的小鼠肺的肺泡表面 修改了 iCAM-1 的分布模式。 5. 定义时间进程 ICAM-1表达的变化及中性粒细胞的相应过程 肺部炎症发展中的侵袭。 6. 测试 抗 ICAM-1 抗体预防中性粒细胞的有效性 渗透并防止肺损伤。 顺利完成 这些目标将加深我们对控制机制的理解 炎症期间中性粒细胞依赖性肺损伤的发展。