Inflammatory Angiogenesis in the Lung

肺部炎症血管生成

• 批准号: 8940518
• 负责人: Venkatesh Sampath
• 金额: $ 0.04万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8940518
• 关键词: Address; Angiopoietin-2; Antibodies; Blood Vessels; Bronchopulmonary Dysplasia; Cells; Clinical Research; Data; Development; Endothelial Cells; Endothelium; Enzymes; Family; Foundations; Future; Genes; Goals; Homologous Gene; Human; ICAM1 gene; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intercellular adhesion molecule 1; KDR gene; Knowledge; Laboratories; Ligands; Link; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Mediating; Molecular; Mus; NADPH Oxidase; Neonatal; Oxidoreductase; Pathogenesis; Phenotype; Pilot Projects; Premature Infant; Publishing; Retina; Risk Factors; Role; Scientific Advances and Accomplishments; Sepsis; Signal Pathway; Signal Transduction; Specific qualifier value; TEK gene; Testing; Therapeutic; Vascular Endothelial Growth Factor Receptor-2; Vascular remodeling; Work; angiogenesis; autocrine; axon guidance; base; cytokine; effective therapy; immune activation; in vivo; inhibitor/antagonist; insight; jagged1 protein; mouse model; neonatal sepsis; notch protein; novel; prevent; programs; public health relevance; receptor; research study; small molecule; toll-like receptor 4

 DESCRIPTION (provided by applicant): Defective lung microvascular arborization is a hallmark of bronchopulmonary dysplasia (BPD), a lung disease that develops in premature infants. Although clinical studies identify sepsis as a major risk-factor for BPD the mechanisms by which sepsis contributes to pulmonary vascular remodeling remain poorly understood. Prior work from our laboratory indicate that bacterial ligands like lipopolysaccharide (LPS) released during sepsis cause endothelial immune activation; a switch from a "quiescent" to an "inflammatory" endothelial phenotype. The overarching goal of this application is to understand the mechanisms by which sepsis-induced pulmonary endothelial immune activation contributes to inflammation and altered angiogenesis in the developing lung. Ongoing studies suggest that NADPH oxidase 2 (NOX2), an oxidoreductase enzyme belonging to the NOX family regulates LPS-induced lung endothelial immune activation. NOX2-mediated endothelial activation promotes lung inflammation by inducing intercellular adhesion molecule-1 (ICAM-1) and cytokine expression. Further, NOX2 also regulates sepsis-induced lung Angiopoietin-2 (ANGPT2) expression, which stimulates angiogenesis. Interestingly, in our mouse model of sepsis lung endothelial activation and inflammation are suppressed in NOX2-/- mice. These pilot data support a key role for endothelial NOX2 in regulating sepsis- induced lung pro-inflammatory angiogenic signaling, which is examined in Aim 1. LPS-mediated ANGPT2 signaling mediates autocrine angiogenesis through its receptor TIE2 in human lung endothelial cells. Further, ANGPT2 signaling through TIE2 induces expression of tip cell endothelial specification markers such as Delta- Like 4 (DLL4) preferentially over stalk cell specification markers like Jagged-1 (JAG1) in vitro. In neonatal mice sepsis robustly induces lung expression of DLL4 and KDR (VEGF receptor). Further, sepsis also programs aberrant angiogenesis in the developing retina. These data provide new insights into the mechanisms by which ANGPT2 regulates sepsis-induced angiogenesis in the neonatal lung; the focus of our studies in Aim 2. Given these preliminary results, we hypothesize that "endothelial NOX2 regulates sepsis-induced lung inflammation and ANGPT2 expression, which directs altered angiogenesis in the neonatal lung by modulating the DLL4-Notch tip vs. stalk cell development ". This hypothesis will be addressed in the experiments of the following Specific Aims: 1) Investigate whether endothelial NOX2 regulates lung endothelial immune activation and inflammation in sepsis; and 2) Determine the role of sepsis-induced ANGPT2 on DLL4-Notch directed lung angiogenesis. We expect that proposed studies will identify endothelial NOX2 and ANGPT2 as key molecular players regulating sepsis-induced inflammation and altered angiogenesis in the neonatal lung. Significant gains in our understanding of endothelial NOX2 signaling, ANGPT2-directed angiogenesis are also anticipated, which will inform future therapeutic strategies to decrease BPD burden in premature infants.

 描述（由申请方提供）：肺微血管分支缺陷是支气管肺发育不良（BPD）的标志，BPD是一种在早产儿中发生的肺部疾病。虽然临床研究确定脓毒症是BPD的主要危险因素，但脓毒症导致肺血管重塑的机制仍知之甚少。我们实验室先前的工作表明，细菌配体如脓毒症期间释放的脂多糖（LPS）导致内皮免疫激活;从“静止”到“炎症”内皮表型的转换。本申请的首要目标是了解脓毒症诱导的肺内皮免疫激活促进发育中的肺中的炎症和改变的血管生成的机制。正在进行的研究表明，NADPH氧化酶2（NOX 2），属于NOX家族的氧化还原酶调节LPS诱导的肺内皮免疫激活。NOX 2介导的内皮活化通过诱导细胞间粘附分子-1（ICAM-1）和细胞因子表达促进肺部炎症。此外，N 0X 2还调节脓毒症诱导的肺血管生成素-2（ANGPT 2）表达，其刺激血管生成。有趣的是，在我们的脓毒症小鼠模型中，N 0X 2-/-小鼠的肺内皮活化和炎症受到抑制。这些初步数据支持内皮N 0X 2在调节脓毒症诱导的肺促炎性血管生成信号传导中的关键作用，这在目的1中进行了检查。LPS介导的ANGPT 2信号转导通过其受体TIE 2介导人肺内皮细胞中的自分泌血管生成此外，在体外，通过TIE 2的ANGPT 2信号传导诱导尖端细胞内皮特化标志物如Delta样4（DLL 4）优先于柄细胞特化标志物如Jagged-1（JAG 1）的表达。在新生小鼠中，脓毒症强烈诱导DLL 4和KDR（VEGF受体）的肺表达。此外，脓毒症还编程发育中的视网膜中的异常血管生成。这些数据为ANGPT 2调节新生儿肺中脓毒症诱导的血管生成的机制提供了新的见解;这是我们在Aim 2中研究的重点。鉴于这些初步结果，我们假设“内皮NOX 2调节脓毒症诱导的肺部炎症和ANGPT 2表达，其通过调节DLL 4-Notch尖端与茎细胞发育来指导新生儿肺中改变的血管生成“。该假设将在以下特定目的的实验中得到解决：1）研究内皮N 0X 2是否调节脓毒症中的肺内皮免疫活化和炎症;和2）确定脓毒症诱导的ANGPT 2对DLL 4-Notch指导的肺血管生成的作用。我们期望所提出的研究将确定内皮NOX 2和ANGPT 2作为调节新生儿肺中脓毒症诱导的炎症和改变的血管生成的关键分子。我们对内皮NOX 2信号传导、ANGPT 2介导的血管生成的理解也有了显著的提高，这将为未来减少早产儿BPD负担的治疗策略提供信息。