Phospholipase A2-mediated surfactant hydrolysis and dysfunction in ALI and ARDS

ALI 和 ARDS 中磷脂酶 A2 介导的表面活性剂水解和功能障碍

• 批准号: 7414068
• 负责人: Robert Duncan Hite
• 金额: $ 36.69万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414068
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Address; Adult Respiratory Distress Syndrome; Air; Alveolar; Binding; Biochemical; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell model; Cells; Clinical; Clinical Data; Educational workshop; Epithelial Cells; Etiology; Family; Film; Functional disorder; Gene Activation; Genes; Hydrolysis; In Vitro; Individual; Inflammatory; Injury; Intervention Studies; Leukocytes; Lipids; Liquid substance; Lung; Lysophospholipids; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Multiple Abnormalities; Newborn Respiratory Distress Syndrome; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Phosphatidyl glycerol; Phosphatidylglycerols; Phospholipase A2; Phospholipids; Play; Production; Property; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Recombinants; Recovery; Regulation; Research Personnel; Respiratory Failure; Respiratory physiology; Role; Sampling; Substrate Specificity; Surface; Testing; Time; Variant; cytokine; in vivo; macrophage; multidisciplinary; neutrophil; pressure; programs; surfactant; surfactant deficiency

DESCRIPTION (provided by applicant): Surfactant deficiency and injury is an important component in the pathogenesis of acute lung injury (ALI)and acute respiratory distress syndrome (ARDS). Analysis of bronchoalveolar lavage (BAL) samples from ALI/ARDS patients reveal multiple abnormalities including decreased total surfactant phospholipid with a disproportionately greater decrease in phosphatidylglycerol (PG). PG is critical to maintain optimal surface activity through its interactions with surfactant protein B (SP-B). Secretory phospholipases A2 (sPLA2) are potent mediators of surfactant injury, and are increased in the BAL fluid in ALI/ARDS. Depletion of PG is a key mechanism in sPLA2-mediated surfactant dysfunction. Identification of specific sPLA2 and mechanisms regulating secretion are unknown in ARDS. This proposal will examine the hypothesis that specific secretory phospholipases A2 released during the inflammatory phase of ALI and ARDS hydrolyze pulmonary surfactant phospholipids, decrease PG and play a major role in limiting endogenous surfactant function and clinical recovery from acute respiratory failure. This hypothesis will be tested as follows: Specific Aim 1. Measure bronchoalveolar phospholipase A2 and surfactant abnormalities during the course of ALI/ARDS. BAL fluid will be obtained from ALI/ARDS patients (n = 80) early in the course of respiratory failure and serial samples will be obtained over the course of respiratory failure. Components of the BAL (cells, surfactant pellet and supernatant) will be analyzed and the associations with important clinical variables of ARDS etiology, respiratory failure and ARDS outcome will be established. Specific Aim 2. Determine the mechanisms regulating sPLA2 expression and secretion. sPLA2 proteins secreted into the BAL will be identified and the regulation of sPLA2 synthesis and release from cell models measured in vitro to test the hypothesis that there is a cytokine driven stimulation of sPLA2 secretion from specific cells in the lung. Cytokine analysis of the BALs in Aim 1 will be used to further direct these studies. Specific Aim 3. Determine the mechanisms that regulate sPLA2-mediated surfactant hydrolysis and dysfunction. The impact of the surfactant proteins (SP) and the alveolar phospholipid forms (bulk aggregates in the subphase and monomolecular films at the air-liquid interface) on sPLA2 hydrolysis, PG depletion and surfactant dysfunction will be examined. Interpretation of the in vivo relevance of these results will be enhanced by measuring SP levels in the BALs from Aim 1. This multicenter, multidisciplinary analysis directly addresses the NHLBI ALI Workshop priority to investigate biochemical predictors of ALI, and is essential to develop effective clinical intervention studies involving suppression of sPLA2 activity and surfactant replacement.

描述（由申请人提供）：表面活性物质缺乏和损伤是急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）发病机制的重要组成部分。分析ALI/ARDS患者的支气管肺泡灌洗（BAL）样本显示多种异常，包括总表面活性剂磷脂减少，磷脂酰甘油（PG）的减少不成比例地更大。通过与表面活性剂蛋白B （SP-B）的相互作用，PG对维持最佳表面活性至关重要。分泌性磷脂酶A2 （sPLA2）是表面活性剂损伤的有效介质，在ALI/ARDS患者BAL液中增加。PG的缺失是spla2介导的表面活性剂功能障碍的关键机制。在ARDS中，特异性sPLA2的鉴定和调节其分泌的机制尚不清楚。本研究将探讨ALI和ARDS炎症期释放的特异性分泌磷脂酶A2水解肺表面活性物质磷脂，降低PG，并在限制内源性表面活性物质功能和急性呼吸衰竭临床恢复中发挥重要作用。这一假设将被检验如下：