SURFACTANT PROTEINS AND LUNG INFLAMMATION

表面活性蛋白和肺部炎症

• 批准号: 6182443
• 负责人: KELLY E GREENE
• 金额: $ 11.16万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6182443
• 关键词: adult respiratory distress syndrome; alveolar macrophages; chemokine; clinical research; diagnostic respiratory lavage; human subject; inflammation; interleukin 8; lipopolysaccharides; lung injury; pulmonary surfactants

Lung inflammation contributes to morbidity in critically ill patients, including those with Acute Respiratory Distress Syndrome (ARDS). Pulmonary surfactant-associated proteins are emerging as important modulators of host defense and alveolar inflammation, in addition to their role in reducing alveolar surface tension. Lung inflammation is characterized by elevated neutrophil and interleukin-8 (IL-8) concentrations in BAL fluid from patients with ARDS. Chemokines, such as IL-8, are potent endogenous neutrophil chemoattractants and are also elevated in BAL fluid from ARDS patients. In addition, lipopolysaccharide (LPS) and lipopolysaccharide-binding protein (LBP) are important mediators of inflammatory responses in the lung. The major goals of this proposal are to elucidate the mechanisms by which surfactant proteins inhibit alveolar inflammation and to determine what role this may play in ARDS patients. My hypothesis is that surfactant proteins bind LPS, blocking the interaction of LPS and LBP, thus inhibiting alveolar inflammation. Furthermore, I postulate that surfactant proteins can bind chemokines and inhibit their proinflammatory effects in the alveolar air space during acute lung injury. I hypothesize SP-A and SP-B levels will predict outcome in patients who are at-risk for developing ARDS and be potentially useful clinical markers. The specific aims of this proposal are: (l) To measure SP-A and SP-B levels in the blood and BALF of patients with ARDS, during their at-risk period and serially after the development of ARDS. Measures of outcome will include development of ARDS, lung injury score, and mortality. (2) To investigate whether SP-A or SP-B alters the interaction between LPS, soluble LPS-binding proteins present in the alveoli, and target effector cells in the lung. My preliminary data suggest that SP-A inhibits LPS/LBP induced IL-8 production in THP-1 cells. I will also examine the interaction between SP-A and LPS/LBP in human alveolar macrophages. (3) To examine if SP-A is able to bind to and modulate the effects of inflammatory chemokines found in BAL fluid during acute lung injury. I will study the interaction between SP-A and specific chemokines like lL-8. My preliminary data show that SP-A inhibits IL-8 induced PMN chemotaxis. I will study the mechanisms by which SPA blocks the proinflammatory effects of IL-8. These studies combine clinically oriented studies in patients with ARDS with basic studies of new mechanisms by which surfactant proteins may modulate inflammation in the lung.

肺部炎症有助于重症患者的发病率， 包括患有急性呼吸窘迫综合征（ARDS）的人。 肺表面活性剂相关蛋白的出现很重要 除了 它们在减少牙槽表面张力方面的作用。 肺部炎症 具有升高的中性粒细胞和白介素-8（IL-8）的特征 来自ARDS患者BAL液的浓度。趋化因子，这样 作为IL-8，是有效的内源性嗜中性粒细胞趋化剂，是 ARDS患者的BAL液中也升高。此外， 脂多糖（LPS）和脂多糖结合蛋白（LBP） 是肺部炎症反应的重要介体。这 该提案的主要目标是阐明 表面活性剂蛋白会抑制肺泡炎症，并确定 这可能在ARDS患者中起什么作用。我的假设是 表面活性剂蛋白结合LP，阻断LP和LBP的相互作用， 因此抑制肺泡炎症。此外，我假设 表面活性剂蛋白可以结合趋化因子并抑制其 急性肺期间肺泡空间的促炎作用 受伤。我假设SP-A和SP-B水平将预测 在危险中开发ARD并可能有用的患者 临床标记。该提议的具体目的是：（l）到 测量患者血液和BALF的SP-A和SP-B水平 ARDS，在其高危期间，并在开发后连续出现 ards。结局的措施将包括ARDS，肺的发展 伤害评分和死亡率。 （2）研究SP-A还是SP-B 改变LP，可溶性LPS结合蛋白之间的相互作用 存在于肺泡中，肺中的靶效应细胞。我的 初步数据表明，SP-A抑制LPS/LBP诱导的IL-8 在THP-1细胞中产生。我还将检查 人肺泡巨噬细胞中的SP-A和LPS/LBP。 （3）检查SP-A是否 能够结合并调节炎症趋化因子的作用 在急性肺损伤期间发现在BAL液中。我将研究 SP-A与特定趋化因子（如LL-8）之间的相互作用。我的 初步数据表明，SP-A抑制IL-8诱导的PMN趋化性。 我将研究水疗中心阻止促炎性的机制 IL-8的影响。这些研究结合了临床方向研究 具有对新机制的基础研究的ARD的患者 表面活性剂蛋白可能调节肺部炎症。