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

基本信息

项目摘要

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(由申请方提供):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。对来自ALI/ARDS患者的支气管肺泡灌洗(BAL)样本的分析显示多种异常,包括总表面活性剂磷脂减少,磷脂酰甘油(PG)减少不成比例。PG通过其与表面活性蛋白B(SP-B)的相互作用对维持最佳表面活性至关重要。分泌型磷脂酶A2(sPLA 2)是表面活性物质损伤的有效介质,并且在ALI/ARDS的BAL液中增加。PG的消耗是sPLA 2介导的表面活性剂功能障碍的关键机制。在ARDS中特异性sPLA 2的鉴定和调节分泌的机制尚不清楚。本提案将检验这一假设,即在ALI和ARDS的炎症阶段释放的特定分泌型磷脂酶A2水解肺表面活性物质磷脂,减少PG,并在限制内源性表面活性物质功能和急性呼吸衰竭的临床恢复中发挥重要作用。该假设将按以下方式进行检验: 具体目标1。测量支气管肺泡磷脂酶A2和表面活性物质异常, 急性肺损伤/急性呼吸窘迫综合征将在治疗过程的早期从ALI/ARDS患者(n = 80)中获得BAL液。 在呼吸衰竭的过程中采集连续样本。将分析BAL的组分(细胞、表面活性剂沉淀和上清液),并确定与ARDS病因学、呼吸衰竭和ARDS结局的重要临床变量的相关性。具体目标2。确定调节sPLA 2表达和分泌的机制。将鉴定分泌到BAL中的sPLA 2蛋白,并在体外测量sPLA 2合成和从细胞模型释放的调节,以测试存在细胞因子驱动的刺激肺中特定细胞分泌sPLA 2的假设。Aim 1中巴尔斯的细胞因子分析将用于进一步指导这些研究。具体目标3。确定调节sPLA 2介导的表面活性剂水解和功能障碍的机制。将检查表面活性剂蛋白(SP)和肺泡磷脂形式(亚相中的大量聚集体和气液界面处的单分子膜)对sPLA 2水解、PG消耗和表面活性剂功能障碍的影响。这些结果的体内相关性的解释将通过测量来自目标1的巴尔斯中的SP水平来增强。这项多中心、多学科分析直接解决了NHLBI ALI研讨会优先调查ALI生化预测因子的问题,对于开发涉及抑制sPLA 2活性和表面活性剂替代的有效临床干预研究至关重要。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Robert Duncan Hite其他文献

Robert Duncan Hite的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Robert Duncan Hite', 18)}}的其他基金

Ohio Consortium Clinical Center for the NHLBI Prevention and Early Treatment of A
俄亥俄州 NHLBI 预防和早期治疗联盟临床中心
  • 批准号:
    8707155
  • 财政年份:
    2014
  • 资助金额:
    $ 36.64万
  • 项目类别:
Ohio Consortium Clinical Center for the NHLBI Prevention and Early Treatment of A
俄亥俄州 NHLBI 预防和早期治疗联盟临床中心
  • 批准号:
    9064199
  • 财政年份:
    2014
  • 资助金额:
    $ 36.64万
  • 项目类别:
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:
    7781293
  • 财政年份:
    2007
  • 资助金额:
    $ 36.64万
  • 项目类别:
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
  • 财政年份:
    2007
  • 资助金额:
    $ 36.64万
  • 项目类别:
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:
    7586232
  • 财政年份:
    2007
  • 资助金额:
    $ 36.64万
  • 项目类别:
Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8328484
  • 财政年份:
    2005
  • 资助金额:
    $ 36.64万
  • 项目类别:
PAC VS CVC FOR MANAGEMENT OF ACUTE LUNG INJURY AND ARDS
PAC 与 CVC 治疗急性肺损伤和 ARDS 的比较
  • 批准号:
    7203818
  • 财政年份:
    2005
  • 资助金额:
    $ 36.64万
  • 项目类别:
ARDS - EDEN Protocol
ARDS - EDEN 协议
  • 批准号:
    7824240
  • 财政年份:
    2005
  • 资助金额:
    $ 36.64万
  • 项目类别:
Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8429029
  • 财政年份:
    2005
  • 资助金额:
    $ 36.64万
  • 项目类别:
Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8020416
  • 财政年份:
    2005
  • 资助金额:
    $ 36.64万
  • 项目类别:

相似海外基金

Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury
组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
  • 批准号:
    10648387
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Inducible HMGB1 antagonist for viral-induced acute lung injury.
诱导型 HMGB1 拮抗剂,用于治疗病毒引起的急性肺损伤。
  • 批准号:
    10591804
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
MAP2K1 AND MAP2K2 IN ACUTE LUNG INJURY AND RESOLUTION
MAP2K1 和 MAP2K2 在急性肺损伤中的作用及缓解
  • 批准号:
    10741574
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Lung epithelial cell-derived C3 in acute lung injury
肺上皮细胞衍生的 C3 在急性肺损伤中的作用
  • 批准号:
    10720687
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS
检查 TRMT1 和 tRNA 甲基化在急性肺损伤和 ARDS 中的作用
  • 批准号:
    10719249
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Development of a new treatment for COVID-19-related acute lung injury targeting the microbiota-derived peptide corisin
针对微生物群衍生肽 corisin 开发治疗 COVID-19 相关急性肺损伤的新疗法
  • 批准号:
    23K07651
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Probing immunovascular mechanobiology in pneumonia-associated acute lung injury at the single capillary level
在单毛细血管水平探讨肺炎相关急性肺损伤的免疫血管力学生物学
  • 批准号:
    10679944
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
The amyloid precursor protein protects against acute lung injury
淀粉样前体蛋白可预防急性肺损伤
  • 批准号:
    10575258
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Role of macrophages and miRNA in regulating lung macrophage polarization and lung pathogenesis during respiratory virus-induced acute lung injury in normal and diabetic Syrian hamsters.
正常和糖尿病叙利亚仓鼠呼吸道病毒引起的急性肺损伤期间巨噬细胞和 miRNA 在调节肺巨噬细胞极化和肺部发病机制中的作用。
  • 批准号:
    10701207
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Roles of N-glycans on neutrophil beta2 integrins in progression of acute lung injury
N-聚糖对中性粒细胞β2整合素在急性肺损伤进展中的作用
  • 批准号:
    10837431
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了